Microelectrode and multiple microelectrodes

ABSTRACT

A medical microelectrode includes an elongate electrode body including a tip section, a main body section and, optionally, a coupling section. The tip section, the main body section and, optionally, the coupling section are embedded in a first electrode matrix element, which is substantially rigid, biocompatible and soluble or biodegradable in a body fluid. Additionally the microelectrode includes a dissolution retarding layer on the first electrode matrix element and/or a second electrode matrix element disposed between the first electrode matrix element and the electrode. Upon dissolution or biodegradation of the first electrode matrix element a drug comprised by the first electrode matrix element or the second electrode matrix element is released into the tissue. Also disclosed are bundles and arrays of the electrodes and their use.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application under 37 C.F.R.§1.53(b) of prior U.S. patent application Ser. No. 13/376,910, filedJan. 31, 2012, by Fredrik Ek et al., entitled “MICROELECTRODE ANDMULTIPLE MICROELECTRODES,” which is a 35 U.S.C. §371 National Phaseapplication based on PCT/SE2010/00152, filed Jun. 3, 2010, which claimsbenefit of Swedish Application No. 0900789-9, filed Jun. 9, 2009. ThePCT International Application was published in the English language. Thecontents of each of the patent applications above-listed areincorporated in full herein by reference.

FIELD OF THE INVENTION

The invention relates to a medical microelectrode and to multiplemedical microelectrodes. In particular, the invention relates to amedical microelectrode, to a bundle of microelectrodes, and to an arrayof microelectrodes and/or microelectrode bundles. The microelectrode,microelectrode bundle and array of microelectrodes or microelectrodebundles of the invention are intended for insertion into soft tissuesuch as the brain, the spinal cord, endocrine organs, muscles, andconnective tissue.

BACKGROUND OF THE INVENTION

Microelectrodes that can be implanted for a long time into the centralnervous system (CNS) have a wide field of application. In thisinvention, the term “electrode” refers to a microelectrode. Inprinciple, all brain nuclei can be recorded from or stimulated by suchelectrodes and their functions monitored. Of particular importance isthe use of a multichannel design in brain nuclei stimulation. In such adesign groups of electrodes or even individual electrodes can beaddressed separately. This allows the user to select those electrodeswhose stimulation produces a therapeutic effect that is improved incomparison with unselective stimulation. Stimulation of the brain orspinal cord can be of particular value in situations when brain nucleiare degenerated or injured. In certain situations it would also beuseful to be able to combine controlled electrical stimulation and localgene transfer. A multichannel design may also allow the user toeffectively measure the effects on multiple neurones and other cellsfollowing systemic or local drug administration or gene transfer. Ofparticular interest is an ability to simultaneously measure the effectsof multiple drug candidates on neuronal function. Monitoring brainactivity through implanted electrodes can also be useful if used tocontrol drug delivery either locally or systemically or othertherapeutic methods such as electrical stimulation of brain nuclei.Multichannel electrodes may also be used to lesion specific andcircumscribed sites in tissue after abnormal impulse activity has beendetected by recordings from the electrodes or by imaging such as fMRI orPET.

To record and stimulate brain structures various forms of implantableelectrodes have been developed (U.S. Pat. No. 6,253,110 B1, U.S. Pat.No. 5,957,958, U.S. Pat. No. 4,573,481, U.S. Pat. No. 7,146,221 B2, U.S.Pat. No. 5,741,319, U.S. Pat. No. 4,920,979, U.S. Pat. No. 5,215,008,U.S. Pat. No. 5,031,621, U.S. Pat. No. 6,993,392 B2, U.S. Pat. No.6,032,062, U.S. Pat. No. 4,852,573, U.S. Pat. No. 3,995,560, U.S. Pat.No. 7,041,492, U.S. Pat. No. 6,421,566 B1, U.S. Pat. No. 4,379,462, U.S.Pat. No. 5,417,719, U.S. Pat. No. 3,822,708, U.S. Pat. No. 5,501,703,U.S. Pat. No. 7,099,718 B1, U.S. Pat. No. 3,724,467; US 2007/0197892A1). However, little attention has been paid to the injuries andcomplications caused by the implantation procedure. Not only can theseconsequences lead to an impaired function of the implant, they may alsoharm the individual in which the electrodes are implanted. The functionof the implanted electrodes and also of the tissue, in which the implantis introduced, may be impaired due to either 1) acute injury of thetissue including bleeding and infarction of the tissue, 2) infection, 3)tissue reactions including inflammation and glial activation caused bythe implantation procedure, 4) long lasting tissue reaction includingglial activation and scar formation isolating the implant, and/or 5)movements between electrode and tissue. These consequences usually occurduring different time intervals during and after the implantation:

1) When implanting microelectrodes in central nervous tissue there is,besides the general risk of open surgery, local risks such as bleedingsand also infarctions of the tissue. Electrodes may punctuate bloodvessels during implantation. This may cause bleeding andvasoconstriction. A strong inflammatory response to blood cells andproteins that leaked into the neural tissue can be thus triggered andmight affect the tissue over extended periods of time. This may in turninduce cell death in the area supplied by the affected vessel. As aconsequence the function of the electrode implant can be impaired.

2) General surgery and particular implantation of artificial devicesalso increase the risk of infections. The surgical area may be infectedat the time of surgery or within the early recovery phase after surgery.The presence of a foreign body material (the implant itself) can alsofunction as a locus minoris for establishing an infection in the tissuesurrounding the electrodes. Tissue infections around implants are ingeneral more difficult to treat with antibiotics than other tissueinfections. Infections close to the implanted electrodes may besidesimpairing the function of the tissue also jeopardize the function of theimplanted electrodes and may in extreme cases require removal of thedevice in order to cure the infection.

In addition to the general protection of systematically administeredantibiotics it would be advantageous to be able to treat infectionsclose to the implanted electrodes locally.

3) Implantation of electrodes into central nervous tissue will due tothe inflicted injury always cause an acute inflammation (Ghirnikar, R Set al., Neurochemical Research 1998, 23(3):329-340; Norton, W T,Neurochemical Research 1999, 24(2): 213-218). This is a normalphysiological reaction and is necessary for the healing process. In thecase of a permanently anchored material in the tissue, the foreign bodymaterial may in addition induce a chronic inflammation that in the worstcases may jeopardize the function of the implant and the tissue. Thematerial and the procedures related to the devices should thereforeminimize chronic inflammation. Another complication that needs to beaddressed is the reaction of the glial cells, particularly theastrocytes and microglia. In the event of perforating injuries to thecentral nervous tissue the astrocytes will proliferate and form anastroglial scar (Eng, F E et al., Neurochemical Research 2000, 25:1439-1451; Polikov, V S et al., 2005, J Neuroscience Methods 148;1-18)). Such a scar may form a capsule-like structure surrounding animplanted electrode and thereby insulate it from the rest of the centralnervous tissue. In cases of a large astroglial capsule this may impairthe function of the electrodes. Thus, the astroglial reaction needs tobe controlled. It should not be totally prevented, however, since thereare indications that lack of astrocytic involvement will actually causea widespread inflammation and tissue reaction worsening the scenario(Eng, F E et al., Neurochemical Research 2000, 25: 1439-1451; Sofroniew,M V et al., Neuroscientist 2005, 11(5): 400-407). Microglia may alsoproliferate after an implantation. These cells have phagocytic capacityand they also release a number of substances that can trigger a chronictype of inflammation. By controlling the microglia the formation of theastrocytic capsule may be reduced. Besides being a health risk, thetissue reactions caused by different types of glia cells may impair thefunction of the implanted electrodes. For example, in case a zone devoidof neurons is created around the electrodes, or a scar is established,much higher current will be needed to activate living neurons. Theincreased current necessary to stimulate neurons at a distance may inturn cause further tissue damage through heat dissipation and/or throughinduction of irreversible reduction and oxidation reactions (see alsoU.S. Pat. No. 6,316,018)

4) The design of the multichannel electrode itself may also triggerdelayed and long lasting tissue responses after implantation at leastpartly due to movements between electrode implant and the tissue. Ofparticular importance is the endogenous movements caused by breathingand by the heart beat. The consequent pulsatile movements are usuallynot uniform in the tissue. For example, the movement caused by the heartbeat around a major artery propagates through the tissue in a nonuniformway. Movements between implant and tissue occurs if the implant is rigidor attached to a rigid structure that do not move along with the softtissue in which the electrodes are implanted. It would therefore be anadvantage to use flexible electrodes that after implantation areanchored in the tissue rather than in the skull or skeleton and that canfollow the movements of the tissue and thereby avoid the frictionbetween electrodes and tissue that otherwise may occur and which maytrigger tissue responses. Movements between electrode and tissue cancause an unstable recording/stimulation situation and thereby impairedfunction of the implant. To reduce the movement between individualelectrodes and the adjacent tissue caused by such endogenous movements,the electrodes should therefore be able to follow the tissue movementsin all directions.

A further complication with multichannel electrodes used for research,in particular multichannel electrodes composed of numerous electrodes isthat it is usually difficult or impossible to identify the neurones orcells recorded/stimulated by the individual electrodes. This hampers theinterpretation of the results considerably since it is not possible torelate the recorded signals to cell type or cell morphology. This alsomay cause problems in interpretation of the effects of stimulation sinceit is not clear which cells were stimulated.

It would thus be a substantial advantage if the aforementionedcomplications could be avoided or at least alleviated.

OBJECTS OF THE INVENTION

An object of the invention is to provide a medical microelectrode, abundle of microelectrodes or an array of microelectrodes or bundles ofmicroelectrodes devoid of one or more drawbacks of microelectrodes,bundles of microelectrodes or arrays of microelectrode bundles known inthe art.

Another object of the invention is to provide a method of studying thepharmacological effect of different concentrations of a drug on livingtissue, in particular nervous tissue such as the brain.

Further objects of the invention will become evident from the followingsummary of the invention, a number of preferred embodiments illustratedin a drawing, and of the appended claims.

SUMMARY OF THE INVENTION

According to the present invention is disclosed a flexible medicalmicroelectrode, a bundle of microelectrodes, and an array ofmicroelectrodes and/or microelectrode bundles, comprising a means forreleasing a drug and/or a gene vector into the tissue into which theelectrode, the bundle or the array is inserted. In the following, theterm “drug” is intended to also comprise “gene vector”. Themicroelectrode of the invention, independent of whether a singleelectrode or comprised by the electrode bundle or the electrode bundlearray of the invention, comprises an electrically conducting electrodebody and an electrically non-conducting electrode matrix elementstabilizing the electrode body during insertion into tissue. Theelectrode matrix element consists of or comprises a material dissolvableand/or degradable in the tissue, that is, in a body fluid. The means forreleasing the drug and/or gene vector is the matrix or is comprised bythe matrix of the invention, such as, for instance, particlesdistributed through the matrix of the invention or a portion of thematrix capable of forming an aqueous solution of the drug upon cominginto contact with body fluid during the dissolution or degradation ofthe matrix. The particles may be drug particles or carrier particlescomprising the drug, for instance microcapsules or porous or layeredmicrospheres comprising the drug. It is also within the ambit of thepresent invention that the drug is linked to the matrix of the inventionor to a particle distributed through the matrix of the invention by abond that is cleaved, in particular hydrolytically or by the action ofan enzyme, upon contact with body fluid. The drug or drug-containingparticles may be distributed throughout the entire matrix element orportions of the matrix element, in particular portions of the matrixelement surrounding an electrode tip. Their distribution may be evenlyor so as to form a concentration gradient.

The microelectrode body of the invention comprises a distal electrodetip section including a sharp or blunt or even spherical tip, a mainbody section extending in a proximal direction from the tip section and,optionally, a proximal coupling section extending in a proximaldirection from the main body section. “Distal” or “first” and “proximal”or “second” relates to the direction of insertion of the electrode intotissue with the electrode tip foremost. Upon insertion of themicroelectrode of the invention into tissue, either as such or comprisedby a bundle of electrodes or an array of electrodes or electrodebundles, and the dissolution or degradation of the electrode matrixelement by body fluid and, in the case of an electrode bundle or anarray of electrodes or electrode bundles, the (additional) dissolutionof the bundle or array matrix or matrices by body fluid, an electrode ofthe invention is transformed into an microelectrode disposed in softtissue. It is preferred for the electrode body, in particular its tipsection, to comprise a means for anchoring the electrode body in thetissue, such as a hook.

It is preferred for sections of the electrode body to be insulated.Particularly preferred is an insulation scheme in which the main bodysection or a major portion thereof is insulated whereas the tip sectionis not insulated.

It is preferred for the diameter of the electrode body, in particularits main portion to be from about 10⁻⁷ m to about 10⁻⁴ m. Except forelements laterally extending from the electrode body, such as hooks foranchoring in tissue, it is preferred for the electrode main body sectionto have a uniform diameter. In particular, the main body section iscircular in a transverse section. Preferably, the main body section iscylindrical or produced from a (cylindrical) metal wire by bending.Alternatively the main body section is preferably flat and rectangularin a transverse section; electrodes with flat thin body sections can beproduced, for instance, by lithographic etching techniques applied to athin layer of metal on an electrically insulating support. Alternativelyflat thin body sections, which may consist of one or more electricallyconducting layers and one or more electrically insulating layers, can becut out by, for instance, laser cutting, from a correspondingly layeredsheet of material. It is also possible for each of such layers to becomposed of electrically conducting portions and electrically insulatingportions. Other geometries than those aforementioned are however notexcluded from the invention.

According to a preferred aspect of the invention the microelectrode bodylacks a proximal coupling section, the main body section being integralwith an electric conductor for establishing electrical contact betweenthe electrode body and an electrode control unit. Preferably theelectrode body and the electrical conductor are of same material, suchas of a thin metal wire of a good electrical conductor. In absence of aproximal coupling section the nominal length of the electrode body ofthe invention is its embedded length in the electrode matrix. In theembodiment lacking a proximal coupling section the proximal end of theelectrode body is defined by the proximal end of the matrix.

In use, the electrode of the invention, independent of whether used as asingle electrode or being comprised by an electrode bundle or an arrayof electrodes or electrode bundles, is electrically coupled to a controlunit. The control unit of the invention feeds an electric current to theelectrode and/or detects an electric current or an electric potentialtransmitted by the electrode, the current or potential arising in thetissue to which it is inserted. The control unit of the inventioncomprises a microprocessor and control software stored in memory of themicroprocessor.

The control unit of the invention can be disposed internally orexternally of the person or animal provided with an electrode, anelectrode bundle or an array of electrodes or electrode bundles of theinvention. It can be in electrically conducting contact with anelectrode of the invention by means of an electrically conducting leador it can be in contact by radiative means. It is also possible for thecontrol unit to be integrated with an electrode of the invention in formof a minute microprocessor disposed at a proximal portion of theelectrode body, the electrode bundle or the array of electrodes orelectrode bundles. The microprocessor may record an electric current orpotential arising in the soft tissue near an electrode tip and store therecord in a memory, which can be read, for instance, after withdrawalfrom tissue.

The present invention is furthermore based on the insight thatadministration of a tissue protecting drug to the tissue surrounding theinserted electrode may benefit the use of the electrode.

In addition, the present invention is based on the insight thatadministration of a drug other than a tissue protecting drug to thetissue surrounding the inserted electrode may benefit the use of theelectrode.

Drug administration through an electrode of the invention is notrestricted to one drug. It is also possible to administer two or moredrugs simultaneously or sequentially. The two or more drugs may belocated in a single electrode matrix element or in differentcompartments or portions of an electrode matrix element, thecompartments being constituted by a single matrix material or bydifferent matrix materials. If the matrix element of the inventioncomprises two or more compartments, they can advantageously be disposedin rotationally symmetric layers extending along the electrode body or aportion thereof or in adjacent matrix sections each extending along aportion of the electrode body. By embedding single electrodes, bundlesof electrodes and arrays of electrodes or electrode bundles in a solidelectrode matrix that is dissolvable or degradable in body fluid, evenelectrodes with very delicate electrode bodies, such as electrode bodiesin the micrometer or even nanometer range, can be inserted into tissuein good condition. One purpose with arranging the electrode matrixelement of the invention thus is to provide for insertion of theelectrode, the bundle of electrodes, and the array of electrodes orelectrode bundles of the invention into tissue while protecting theintegrity of the electrode body and tip, and if present, of tissueretaining elements, such as hooks, extending from the electrode tip orbody. For easy insertion, the electrode matrix element is preferablynarrowing in a distal direction. At its distal end the electrode matrixelement has preferably the form of a blunt or sharp tip. The tip may beconical or about conical but may also be flattened. In contrast, amatrix enclosing a plurality of electrodes or electrode bundles of theinvention so as to form an array of electrodes or electrode bundles,which electrodes or electrode bundles comprise and are already embeddedin one or more electrode matrix elements, is termed array matrixelement.

A preferred axial length, that is, a length in the intended direction ofinsertion of the electrode into tissue, of the electrode and/or theelectrode matrix, the electrode bundle and/or the electrode bundlematrix, the electrode array or electrode bundle array and/or and thecorresponding matrix is 100 mm or less or 50 mm or even 15 mm or less.Exceptionally, the axial length of any of said electrodes, electrodearrays, electrode bundles and/or corresponding matrices is more than 100mm.

Most important, the electrode matrix element of the invention is not athin coat on the electrode body but is an element physically stabilizingthe electrode body including its tip and, if present, tissue retainingelements during insertion into tissue and for a desired period of timeafter insertion. The electrode matrix element of the invention enclosingand stabilizing an electrode or an electrode bundle is preferablyrotationally symmetrical. A preferred shape is that of a minusculeprojectile with a pointed tip and a flat rear base. It is preferred forthe electrode matrix element to be disposed rotationally symmetrical inrespect of the electrode or electrode bundle, sharing its longitudinalaxis with that of the electrode body or electrode bundle. Accordingly,the electrode matrix element of the invention is preferably circular orelliptical in a section transverse to its longitudinal axis. Accordingto the invention it is preferred that a transverse diameter or shortellipse diameter of the electrode matrix of the invention issubstantially larger than the diameter of an electrode body enclosed byit, such as larger by a factor of 2, 5, 10, and even 25 or more.

According to the invention, it is important that the combination of a)an electrode, an electrode bundle, or an array of electrodes orelectrode bundles, and b) one or several matrix elements has sufficientphysical stability or rigidity to allow it to be inserted into softtissue along a generally straight path, which is opened up by the actionof the respective tip on the tissue. The tip thus cuts into the tissue.This method of placing the electrode, the bundle of electrodes, thearray of electrodes or of bundle of electrodes of the invention at adesired location in soft tissue is substantially different fromimplantation, which would require opening up the path by surgery. If notsupported by the matrix element(s) the electrode, the electrode bundleor the array of electrodes or electrode bundles could not be insertedinto tissue due to insufficient rigidity causing the device to beinserted to bend and thereby to deviate from the desired insertion path.

According to a preferred aspect of the invention, the surface of thematrix is provided with a layer of material facilitating insertion, suchas a material of low friction in contact with soft tissue. On the otherhand, the insertion facilitating layer should readily dissolve and/orbeing degraded upon insertion. A preferred insertion facilitating layermay comprise or consist of a lipid having a melting point a few degreeshigher than the temperature of the tissue into which is intended to beinserted, such as a melting point of 40° C. to 43° C. Additionally oralternatively the layer on the surface of the matrix may be designed tosubstantially delay dissolution and/or degradation of the matrix, suchas by 1 min or 10 min or more. A suitable layer of this kind can beformed by polymers used for tablet coating in the pharmaceuticalindustry for slow release in an aqueous environment of about pH 7-7.5.

According to a preferred aspect of the invention, the electrode body isfully enclosed by the electrode matrix element except for at itsproximal end, the electrode tip being disposed at a distance in aproximal direction from the tip of the electrode matrix.

According to another preferred aspect of the invention it is desirablefor the electrode body of the invention to have, once implanted, freedomof movement of portions thereof not only in a lateral direction but alsoin a longitudinal direction, independent of whether pertaining to asingle electrode or of an electrode comprised by an electrode bundle orby an electrode bundle array. Thereby negative effects of non-uniformmovements of surrounding tissue on the electrode body are avoided, inparticular effects tending to dislocate the electrode body and/or tomake it move in a manner damaging surrounding tissue. What is saidherein about the freedom of movement of the electrode body relates to anelectrode body in the tissue upon dissolution and/or degradation of theelectrode matrix, that is, once the electrode body is no longerconstrained in its movement by the electrode matrix element. Inparticular, the present invention is based on the insight that it isadvantageous for such an electrode body to comprise portions capable ofmovement relative to each other so as to increase or decrease theirdistance along the electrode. The invention is also based on the insightthat, for their implantation or insertion, in particular theirimplantation or insertion in a desired configuration, the electrode bodyof the invention, independent of whether pertaining to an electrodebundle or an array of electrode bundles or an array of single electrodesand electrode bundles or not, does require configurationalstabilization. In this application, “configuration” relates to thethree-dimensional forms or states that an electrode of the invention canassume or be forced to assume due to its flexibility. According to theinvention configurational stabilization is provided by at least partialembedment of the electrode in the electrode matrix element, which isremoved by dissolution in body fluid or by degradation once theelectrode has been disposed in a desired location in soft tissue. Thusthe electrode matrix or electrode support material is one that isdissolvable or degradable in body fluid, that is, in an aqueousenvironment but also, if the electrode is inserted into fatty tissue, inan environment rich in fat. After dissolution or degradation theelectrode matrix material or degradation products thereof, respectively,is cleared from the insertion site by solute transport mechanismsoperating in living tissue and/or is metabolized. The electrode matrixelement of the invention may be of a material that must to be degradedto make it soluble or to enhance its solubility in body fluids; suchdegradation is effected by mechanisms operative in living tissue and/orby adjuvant, such as an enzyme, comprised by the electrode.

According to the present invention is thus disclosed a medicalmicroelectrode for insertion into soft tissue, comprising anelectrically conducting elongate electrode body having a first, proximalend and a second, distal end, the electrode body comprising a tipsection extending from its distal end, a main body section extending ina proximal direction from the tip section, and, optionally, a couplingsection extending in a proximal direction from the main body section,wherein the tip section, the main body section and, optionally, thecoupling section are embedded in a first electrode matrix element, whichis substantially rigid, biocompatible and soluble or biodegradable in abody fluid, further comprising one or both of: a dissolution retardinglayer on the first electrode matrix element; a second electrode matrixelement, which may optionally comprise two or more sections, disposedbetween the first electrode matrix element and the electrode; wherein adrug capable of being released upon dissolution or biodegradation of thefirst electrode matrix element is comprised by the first electrodematrix element or the second electrode matrix element. The drug can bedispersed or dissolved in the matrix or be comprised by the matrix inmicroencapsulated form or comprised by a rod of biodegradable materialor a material dissolvable in body fluid.

In a preferred embodiment the microelectrode comprises an anchoringmeans disposed at the tip section.

In another preferred embodiment the electrode body comprises anon-conducting core, one or more electrically conducting layers on thecore, an insulating layer on the one or more electrically conductinglayers and, optionally, one or several passages through the insulatinglayer perpendicular to the core permitting electrical contact with theelectrically conducting layer(s).

It is preferred for the tip section, the main body section and, ifpresent, the anchoring means to be fully embedded in the first electrodematrix element.

In a preferred aspect of the invention the first electrode matrixelement comprises two or more sections differing in their dissolution ordegradation rate.

A preferred diameter of the electrode body is from about 10⁻⁷ m to about10⁻⁴ m.

According to another preferred aspect of the invention the main bodysection comprises portions capable of movement relative to each otherupon dissolution or degradation of the first electrode matrix element,so as to increase or decrease their distance along the electrode body.

According to a further preferred aspect of the invention the firstelectrode matrix element comprises a first drug and the second electrodematrix element comprises a second drug.

Furthermore, according to the present invention, is disclosed a medicalmicroelectrode bundle comprising two or more electrodes of the inventionwith their electrode bodies disposed substantially in parallel andsharing said first electrode matrix element or comprising a bundlematrix element enclosing said first matrix elements. According to apreferred aspect of the invention the microelectrode bundle comprises adissolution retardation coating on the shared first electrode matrixelement or on the bundle matrix element. It is preferred for theproximal ends of the two or more electrodes of the bundle to be disposedin substantially the same plane. According to another preferred aspectof the invention the microelectrode bundle comprises, in addition to theshared first electrode matrix element or the bundle matrix element abundling means disposed at or near the proximal ends of the electrodes,which bundling means does not comprise a dissolvable or biodegradablematrix. The microelectrode bundle of the invention may comprise one ormore optical fibres. According to a further preferred aspect of theinvention two or more first or second electrode matrix elements of amicroelectrode bundle comprise different amounts of a drug or differ intheir drug release properties. Insertion of the microelectrode bundle ofthe invention into soft tissue is facilitated by use of a bundleinsertion element such as a rod. For such use the microelectrode bundleof the invention is provided with a releaseable coupling means.

Furthermore, according to the present invention, is disclosed an arrayof medical microelectrodes or microelectrode bundles comprising two ormore microelectrodes of the invention or two or more microelectrodebundles of the invention, wherein the two or more microelectrodes or twoor more microelectrode bundles are disposed interspaced on a face of asolid support. It is preferred for the two or more microelectrodes ortwo or more microelectrode bundles of the array to be embedded in asubstantially rigid biocompatible array matrix element, which is solubleor biodegradable in a body fluid. Preferably the dissolution ordegradation rate of the array matrix element in said body fluid ishigher than the dissolution or degradation rate of said first electrodematrix element or bundle matrix element. The array matrix element mayadditionally comprise a dissolution or degradation retardation coat onthe array matrix element.

Single Electrodes

The microelectrode body, which is preferably about circular or ellipticin cross section, comprises an electrically conducting or non-conductingcore, an electrically conducting layer on the core if the core isnon-conducting, and an insulating layer on the electrically conductinglayer or core. However, other electrode bodies with other crosssections, such as rectangular or polygonal, may also be used.Alternatively, the electrode body comprises or consists of anon-conducting polymer tube filled with an electrically conductingmaterial. A non-conducting core is preferably a natural, semi-syntheticor synthetic polymer filament, such as a filament of silk, cotton,artificial silk (cellulose acetate), polyethylene, polypropylene,polyamide, etc. A conducting core is a thin metal wire of, for instance,gold, platinum, titanium, iridium, an alloy comprising theaforementioned or other metals, stainless steel or an electricallyconductive polymer fibre. The electrically conducting layer on anon-conducting core consists or comprises a metal of high electricalconductivity, such as silver, gold and or a suitable metal alloy, e.g.platinum-iridium, deposed on the core by, for instance, ion sputteringor evaporation techniques. In case of a gold layer adhesion to the corecan be improved by interposition of a chrome or tungsten layer betweenthe gold layer and the core. Such interposition is also feasible withother metal layers. The thickness of a deposed metallic conductive layeris from 0.1 μm to about 100 μm. Alternatively, the electricallyconducting layer may consist or comprise an electrically conductingpolymer. The insulating layer comprises or preferably consists of anelectrically non-conducting polymer. In most applications, the diameterof the electrode body is from about 10⁻⁷ to about 10⁻⁴ m, preferablyless than about 2.5·10⁻⁵ m. However, in some applications the electrodebody may have a larger diameter, in particular if the electrode isintended for producing lesions of soft tissue.

The insulation layer of the electrode body extends preferably from thebody's proximal end to the body's distal end, that is, the entireelectrode body is insulated. Examples of materials suitable forinsulation are glass, polyvinyl formal, epoxy resin, poly(p-xylylene),polyamide, silicone rubber or a water-resistant lacquer. It is howeverpossible to provide along the electrode body passages through theinsulation layer to the conducting core, in particular passages disposedabout perpendicular to the core.

If electrical stimulation of a larger volume of tissue is intended, itmay be preferred not to insulate the portion of the electrode bodyintended for insertion into the target tissue. Alternatively, theelectrode body may comprise regions that are not insulated to allowstimulation/recordings of multiples sites within the tissue.

To facilitate insertion into tissue the electrode body of the inventionis at least partially embedded in a rigid or substantially rigid elementor body of a biocompatible matrix material termed electrode matrixelement. The electrode matrix material is preferably macroscopicallyuniform. The embedment comprises at least a portion of the electrodebody, more preferred the electrode tip and a portion of the electrodebody extending from the tip. “Substantially rigid” indicates that thebody may be only slightly resiliently flexible. The electrode matrixelement or body comprises or consists of a solid matrix material that issoluble or biodegradable in a body fluid, in particular an aqueous bodyfluid but, alternatively, also in one rich in fat. Incorporation of theelectrode in the matrix body not only allows the electrode to beinserted or implanted into tissue and to be disposed therein in adesired disposition but also in a desired configuration. The electrodebody or at least portions thereof may be configurationally locked in theelectrode matrix element. After dissolution or degradation of theelectrode matrix element the electrode body may retain its initial orfirst configuration in tissue or assume or made to assume a secondconfiguration or an unlimited number of configurations. By “initialconfiguration” is meant the configuration of the electrode or theelectrode body or a section of the electrode body embedded in a matrix.A curvy or other non-straight shape of the electrode body improves theanchoring of the electrode in tissue, since tissue cells will grow closeto the body. In contrast to a straight electrode body, a curvy or othernon-straight electrode body does improve the ability of the electrode ofthe invention to move, without being dislocated, in unison withnon-uniform movements of the tissue into which the electrode isimplanted or inserted. According to an important aspect of the inventionthe matrix body comprises a drug or gene vector capable of release to abody fluid, in particular an aqueous body fluid, upon implantation ofthe electrode. The drug may be released from the matrix body prior toits the dissolution or degradation, in particular at least partially.The drug may be comprised, for instance, by a matrix of open structure,such as a matrix provided with open microchannels. The drug may bereleased from the matrix concurrently with the dissolution ordegradation of the matrix. The drug can be present in the matrix in adispersed or dissolved state, in a state adsorbed to the pore walls of aporous matrix and even as a prodrug linked by a covalent bond to thematrix. Alternatively the drug can be present in the matrix inmicroencapsulated form or comprised by a body, which dissolves in a bodyfluid or is biodegradable in human tissue. Exceptionally, the drug canbe comprised by a body separate of the electrode matrix element, whichbody is can be either dissolvable in a body fluid or not, or can bebiodegradable or not. The drug is preferably one that protects fromdamage the tissue into which the electrode is inserted and/or assiststhe recovery of damaged tissue. Independent thereof, the drug of theinvention is a drug exerting a pharmacological effect on tissuesadjacent to the inserted electrode, in particular nerve tissue, mostparticularly tissue of the nuclei or white matter of the brain and thespinal cord.

In the embodiment of the electrode body and thus the electrode of theinvention having a configuration permitting the distance from itsproximal end to its distal end to be increased and/or decreased onceimplanted in human or animal tissue, the adoption of a secondconfiguration by the electrode body can be provided by several means. Ifthe electrode body is resiliently flexible or comprises resilientlyflexible portions it may be embedded in the electrode matrix element ina compressed or tensioned state so that, upon dissolution of theelectrode matrix element after implantation of the electrode in tissue,the electrode body may expand or contract, respectively.

In its initial configuration the electrode body, while generallysubstantially extending in one direction, may be straight or compriseregular or irregular bends, spirals, loops, zigzag sections, etc. Inother words, in its initial conformation, the length of the electrodebody may be substantially greater than the distance between its proximaland distal ends. By substantially greater is meant a length such as by 2percent or more, in particular by 5 percent or more, even by 20 percentor more, and up to by 50 percent or more, of the distance between itsfirst and second electrode ends. The tip section of the electrodeextending from the second, distal end however preferably has a straightor only slightly bent configuration.

The distal end or tip section of the electrode, which is not insulated,can be of any suitable shape. Sharp tips are particularly advantageousif the electrode is intended for recording purposes. If the electrode isintended to be used for stimulation it is preferred that the electrodetip section does not comprise sharp edges but rather has a smoothcontour to reduce the erosion of the tip section. Optionally the surfacearea of the electrode tip section may be enlarged by roughening toincrease the contact with surrounding cells and decrease the impedanceof the electrode. A rough surface can be obtained by, for instance,coating the electrode with platinum black or by etching.

At its proximal end, the electrode body is in electrically conductivecontact with electronic equipment via an insulated flexible electricalwire.

The tip section and/or the main body section the electrode of theinvention can be provided with anchoring means, such as rough surfaceportions or surface portions promoting adhesion to surrounding tissue.Electrode body sections capable of adhering to adjacent tissue may evenbe of a kind, for instance of titanium or having portions coated withtitanium oxide, allowing tissue adhesion or ingrowth. Thin laterallyextending filaments attached to the tip section, which are disposed in aproximal direction during the insertion procedure and then unfold onretracting the electrode for a short distance, are known (WO2007/040442); the electrode of the invention may be provided with suchfilaments to anchor it in human or animal tissue. It is preferred thatthese thin laterally extending filaments have a diameter equal to orpreferably less than the diameter of the electrode body, and/or to be ofa length to allow them to laterally protrude for a suitable distance,such as up to fifty μm or more, and even up to hundred μm or more, fromthe electrode. It is preferred for the laterally extending filament(s)to additionally function as electrodes, in which case at least their tipis not insulated. It is also preferred for a laterally extendingfilament to comprise or consist of the electrically conductive materialof the electrode, and for that material to be integral with the materialof the electrode body. It is however also within the scope of theinvention that the lateral extending filaments are of a materialdifferent from that of the electrode. Since laterally extendingfilaments do not hinder insertion of the matrix-embedded electrode intotissue due to them being enclosed by the electrode matrix, they mayextend from the electrode in any direction, such as a distal, radial orproximal direction. It is also possible for an electrode to comprise amultitude of laterally extending filaments and for those filaments toextend in one or several directions from the electrode. Likewise, it ispreferred for the core or supporting tube of the electrode to be of thesame material as the tip section and to be integral with it. In anelectrode equipped with protruding elements at its tip section suchwithdrawal may allow the protruding elements to become anchored in thetissue and to make the electrode resist withdrawal. Pushing an electrodeof appropriate tip design, such as a tip bending or slanting away fromthe long axis of the electrode body defined by the straight lineconnecting its first and second ends further into the tissue may causeits tip portion to deviate sideways from the direction of the long axis.

The electrode of the invention is intended for insertion into softliving tissue, in particular brain and spinal cord tissue, but also, forinstance, into the liver, the kidneys, skeletal muscles, heart muscles,visceral muscles, and connective tissue. The electrode of the inventioncan be used for recording and/or for nerve-stimulating purposes. If usedfor recording purposes, an electrode wire of the invention can beequipped with a miniaturized preamplifier. It is preferred for theamplifier to be arranged at a short distance from the tip, such as atthe junction of the body and tip sections, to improve the signal tonoise ratio.

To further facilitate insertion into soft tissue, it is preferred that amicro-manipulator rod or similar is attached to the matrix or embeddedin the matrix near or at the proximal end thereof. Releaseableattachment of the micro-manipulator may alternatively be provided by adocking means comprised by the proximal coupling section of theelectrode.

Electrode Bundles

In certain applications it is an advantage to use multiple, suitablyarranged electrodes of the kind disclosed above.

The combination of two or more electrodes of the invention in a commonor shared matrix body is termed electrode bundle. The shared matrixforms an electrode bundle matrix element. It is soluble or biodegradablein a body fluid. An important feature of the electrode bundle of theinvention is that at least two electrodes comprised by the bundle haveto be electrically insulated from each other. It is though preferred forall or substantially all electrodes of the bundle to be electricallyinsulated in respect of each other. The bundle matrix element is rigidor substantially rigid. The purpose of the bundle matrix element is toimpart physical stability to the electrode bundle so as to allow it tobe inserted into tissue along a substantially straight path. This allowsdisposing a plurality of electrodes in a desired soft tissue region. Itis also within the ambit of the invention to provide an electrode bundlewith conventional straight electrode wires, optical wires, contractilepolymers or stiff electrode chips containing electrodes and/orelectronics, which elements are at least partially disposed in thematrix body. Optionally, the electrode or bundle matrix elementcomprises two or more sections of matrix materials differing in theirdissolution rate in an aqueous environment. A sectioned matrix elementfor an electrode bundle of the invention corresponds in respect of itsfeatures to the electrode matrix element of the invention describedabove. In addition to the shared electrode bundle matrix element of theinvention one or more electrodes of the bundle, in particular allelectrodes of the bundle, may be provided with an electrode matrixelement of the invention; in such case the electrode bundle matrixelement joins or even may enclose the one or more electrode matrixelements of the bundle

It is preferred for electrode bodies comprised by an electrode bundle ofthe invention to be of varying length and, if the electrode bundlematrix element or body is of rotationally symmetric form, for instancecylindrical, to be symmetrically arranged in respect of the central axisthereof. It is preferred for the longest electrode bodies to be disposedat a short distance from the central axis and for the shorter ones at agreater distance from the axis so as to make the totality of their tipsreflect the form of the matrix tip. Their proximal ends are preferablydisposed in or near a plane transverse to the rotational axis. It ishowever also within the scope of the invention to arrange the electrodebodies in a manner forming a unilaterally slanting or otherwise notsymmetric electrode bundle tip. Thus the electrode bundle matrix elementmay be tapering in a distal direction so as to form, for instance, aconical or flat triangular terminal distal portion. The terminal distalportion of the electrode bundle matrix element can have a blunt shape tominimize the risk of vascular rupture during insertion of the electrodebundle into soft tissue.

According to another preferred aspect of the invention the electrodebundle comprises one or more optical fibres to allow radiativestimulation of the tissue or components thereof and/or for recordingradiation emanating from surrounding tissue. In a manner correspondingto that of the electrode bodies the one or more optical fibres are keptin a selected position in the electrode bundle by means of the electrodebundle matrix element.

According to a further preferred aspect of the invention two or moreelectrode bodies in the matrix-embedded electrode bundle of theinvention can be joined at or near their first ends by a base plate of,for instance, a ceramic or polymer material. Electrodes so joined may beof same or different length. The base plate may be equipped withelectronic components such as amplifiers and be connected to electronicsoutside the tissue for stimulation and recording purposes via a cable ortelemetrically; it may also be used for mounting a means for receiving amicromanipulator.

According to a still further preferred aspect of the invention theelectrode bundle comprises one or more contractile bimetallic elementscapable of changing their shape, for instance to bend, when electriccurrent is passed through them. Such contractile elements can be used tocontrol the insertion path of the matrix-embedded electrode bundle.

For insertion of the electrode bundle of the invention into soft tissuea micromanipulator is attached or attachable to a proximal end portionof the electrode array, from which it extends in a proximal direction.

The stiffness of the electrode bundle of the invention provided by theelectrode matrix shared by the bundle electrodes facilitates itsinsertion into tissue. Upon insertion, the electrode matrix may bequickly or slowly dissolved or degraded. A desired dissolution ordegradation rate can be selected by using an appropriate matrixmaterial. Thereby the electrode body becomes capable of lateraldisplacement in respect of neighbouring electrode bodies.

Arrays of Electrodes and/or Electrode Bundles

According to the invention two or more matrix-embedded electrodes and/orelectrode bundles disposed in parallel or about in parallel can bejoined by a substantially solid array matrix or glue that can dissolvein or be degraded by an aqueous medium such as a body fluid but also ina body fluid rich in fat such as nerve tissue. The array matrix must bebiocompatible. Suitable materials include glues on a carbohydrate or aprotein basis, such as alkylated and/or carboxylated cellulosederivatives, amylose, and gelatin, but can also be of a differentnature, such as polyvinyl alcohol, polyvinylpyrrolidone, and alkalisalts of polyacrylic acid. In this manner electrodes and/or electrodebundles can be arranged in an array in a desired geometric patternsuitable for implantation. Thereby the time required for implantation isconsiderably shortened compared with that for the same geometric patternobtained by implantation of individual electrodes and/or electrodebundles. One or more matrix-embedded electrode bodies and/or electrodebundles of the invention in such an array can be substituted by two ormore of matrix-embedded electrode bodies of the invention that aretemporarily or permanently kept in a fixed relationship in respect ofeach other. The means for keeping them in such fixed relationship maycomprise or consist of one or more matrix materials of the invention orbe independent thereof. If independent thereof, the means can be onethat dissolves and/or disintegrates more slowly in an aqueousenvironment than any other matrix material of the matrix-embeddedelectrode bundle or a permanent one, such as a means keeping theelectrode bundle of WO 2007/040442 in a fixed relationship. Similarlyone or more electrode bundles in the electrode array of the inventioncan be substituted by one or more electrode bundles of WO 2007/040442. Asuitable distance between electrode bundles in an electrode bundle arrayof the invention is from 50 μm to 500 μm or more. In one embodiment,individual matrix embedded electrode bodies of an electrode bundle ofthe invention are mounted in a interspaced configuration with theirproximal ends secured in a base plate that is dissolvable in an aqueousbody fluid. This arrangement facilitates insertion into tissue of thebundle or of an array comprising two or more of such bundles.

The array of matrix-embedded electrode bundles or of a combination ofmatrix-embedded electrodes of the invention and matrix-embeddedelectrode bundles of the invention is suitable for long-lastingstimulation, multi-channel recordings of electrical neuronal activityand levels of transmitter substance or other bioactive molecules throughmeasurements of redox reactions and precise lesions of the tissue forscientific, medical and animal care purposes.

According to the present invention a preferred means for drug release isa matrix element. A drug is embedded in the matrix by dissolution,dispersion, linkage via a biodegradable linker or by any other suitablemanner.

Another preferred means for drug release is a compartment such as amicrosphere or other microparticle dispersed in the matrix.

A further preferred means for drug release is an electrode coatingcomprising the drug, the electrode coating being enclosed by the matrix.

The drug of the invention includes but is not limited to an agentaffecting physiological and/or pathological processes in the tissue intowhich the electrode, the electrode bundle or the array of electrodebundles of the invention is inserted.

The array matrix element or body of the invention is of a biocompatiblematerial that dissolves in an aqueous environment such as body fluids.Prior to dissolving, it may swell or not. The array matrix element ispreferably oblong in a distal direction, that is, forms the frontal partof the matrix-embedded electrode that is first introduced into thetissue. It can be shaped, for instance, as a bar of a length at leastequal to the distance between the first and second ends of the electrodein its initial conformation. The array matrix element is preferablytapering in the direction of its distal end. Its distal end section ispreferably about conical to facilitate insertion into soft tissue. Itsdistal tip may have a sharp or a blunt shape. A blunt shape minimizesthe risk of vascular rupture during insertion while a sharp tip willreduce the resistance of the tissue against insertion. The shape of thearray matrix element permits to follow a straight insertion track linewhen inserting the electrode deep into the soft tissue, and therebyenables the user to accurately position the electrodes of the array inthe tissue. A wettable matrix will also constitute a slippery surfaceminimizing strain forces in the tissue, longitudinally along the sidesof the array matrix element.

To permit, in animal studies, rapid screening of effective drugconcentrations or screening of an effective drug release time course,individual electrodes or electrode bundles of an array of electrodes orof electrode bundles, respectively, can be embedded in one and the samematrix element containing one drug in one concentration; alternativelytwo or more of such individual electrodes or electrode bundles can beembedded in two or more matrix elements, respectively, the matrixcontaining a corresponding number of concentrations of said one drug ora corresponding number of different drug in the same concentration or indifferent concentrations. By this arrangement screening of differentconcentrations of one drug or of different drugs can be carried out byuse of one array of this kind. It is also possible to coat the matricesof two or more electrodes or electrode bundles intended forincorporation into an array with a corresponding number of coatingsdiffering in their barrier properties against humidity, thus more orless delaying the degradation or dissolution of matrices so protected.

According to preferred embodiment of the invention, in an matrix elementcomprising two or more sections, the sections may be arranged so thatthere is one outer section fully or partially enclosing one or moreinner sections in which an electrode of the invention is embedded. Thedrug or drugs intended for release are only comprised by the innersection(s). The inner matrix element section(s) are preferably notenclosing the electrode tip while the outer section encloses the tip aswell as the inner sections. The outer section thus is intended primarilyfor protecting the physical integrity of the electrode during insertioninto tissue, and has a dissolution or degradation profile substantiallydifferent from that of the inner section(s), that is, is dissolvedand/or degraded substantially more readily than the inner matrixsection(s), such as by a factor of 5, 10 or even 100.

According to a further preferred embodiment of the invention thedistance between the tips/distal ends of electrodes in electrode bundlesor in arrays of electrode bundles after dissolution or degradation ofthe matrix or matrices enclosing them should be at least 200 μm or more,preferably 500 μm or more. This final implantation distance is obtainedby unfolding of the electrodes in a bundle by means of a plug ofwater-swellable polymer material disposed in the centre of an electrodebundle, that is, with the electrodes of the bundle surrounding it.Alternatively or additionally, the final implantation distance isobtained by using electrodes with a main body section incorporated in amatrix in an axially compressed and/or radially bent state. Upondegradation and/or dissolution of the matrix they are returning to theiroriginal uncompressed and/or non-bent state.

Matrices

Polymers which can be used for forming the matrix include ones that canbe dissolved and cured or polymerized on the medical device or polymershaving relatively low melting points that can be blended withtherapeutic agents. Such biocompatible polymers known to the artinclude, but are not limited to: gelatine, collagen, gum Arabic,polyglycolic acid, carboxyvinyl polymer, sodium polyacrylate,carboxymethyl, sodium carboxymethyl cellulose, pullulan,polyvinylpyrrolidone, karaya gum, pectin, xanthane gum, tragacanth,alginic acid, polycarbonates, polyoxymethylenes, polyimides, polyethers,cellulose, cellulose acetate, cellulose butyrate, cellulose 65 acetatebutyrate, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose collagens, chitins, polylaetic acid,polyglycolic acid, and polylaetic acid-polyethylene oxide copolymers,polyamides, polyorthoesters, polyanhydrides (PAN), polycaprolactone(PCL), maleic anhydride copolymers, polyhydroxybutyrate copolymers, aswell as mixtures and blends thereof. Examples of the above include, butare not limited to, poly 1,3-(bis(p-carbophenoxy)propane anhydride((PCPP) an aromatic polyanhydride), polymer formed from thecopolymerization of pCPP with sebacic acid (i.e., a copolymer of anaromatic diacid and an aliphatic diacid) and polyterephthalic acid(i.e., polyterephthalic anhydride, and aromatic anhydride),poly(L-lactide) (PLLA), poly(D,L-lactide), (PLA), polyglycolide(PGA),poly(L-lactide-co-D,L-lactide) (PLLAJPLA),poly(L-lactide-co-glycolide)PLLN PGA),Poly(D,L-lactide-co-glycolide)(PLAJPGA), poly(glycolideco-trimethylenecarbonate) (PGNPTMC), polyethylene oxide (PEG), polydioxanone (PDS),polypropylene fumarate, poly(ethyl glutamate-co glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), polycaprolactone (PCL),polycaprolactone co-butylacrylate, polyhydroxybutyrate (PHBT) andcopolymers of polyhydroxybutyrate, poly(phosphazene),poly(D,L-lactide-co-caprolactone) (PLN PCL),poly(glycolide-co-caprolactone) (PGAJPCL), poly(phosphate ester),poly(amino acid) and poly(hydroxybutyrate), polydepsidpeptides, maleicanhydride copolymers, polyphosphazenes, polyiminocarbonates, poly[97.5%dimethyl-trimethylene carbonate)-co-(2.5% trimethlyene carbonate)],cyanacrylate, polyethylene oxide, hydroxypropylmethylcellulose,polysaccharides such as hyaluronic acid, chitosan and regeneratecellulose, Poly(ethylene-co-vinyl acetate) (EVA); isobutylene basedcopolymers of isobutylene and at least one other repeating unit (e.g.,butyl acrylate, butyl methacrylate, substituted styrenes (e.g., aminostyrenes, hydroxy styrenes, carboxy styrenes, sulfonated stryenes, etc.)homopolymers of polyvinyl alcohol, copolymers of polyvinyl alcohol andat least one other repeating unit, such as a vinyl cyclohexyl ether,hydroxymethyl methacrylate, hydroxyl or amine terminated polyethyleneglycols, etc.), acrylate based copolymers (e.g., methacrylic acid,methacrylamide, hydroxymethyl methacrylates, etc.), ethylene vinylalcohol copolymers, silicone based copolymers of an aryl or alkylsiloxane and at least one repeated unit (e.g., butyl acrylate, butylpolymer, (e.g., a copolymer of butyl methacrylate and PEG). (US2005/0187146 A1).

Preferred materials may vary depending on the type of application andexamples are listed in the sections describing different embodiments ofthe invention.

Bioactive and biocompatible polymers may be combined non-covalently toform polymer blends and covalently to form interpenetrating polymernetworks, copolymers and graft polymers. Preferred combinations ofbioactive and biocompatible polymers include, but are not limited to,polyurethanes, heparan sulfate and RGD peptides, polyethylene oxides,chrondroitin sulfate and YIGSR peptides, silicone polymers, keratansulfate and VEGF biomimetic peptides, SIBS, perlecan and IKVAV peptidesand N-butyl methacrylate, heparin and fibrin fragments.

Optionally, the electrode or array matrix of the invention comprises twoor more sections of matrix materials differing in their dissolution ratein an aqueous environment. For example, in certain applications it isadvantageous for the matrix to comprise or consist of two sections, aproximal section and a distal section, wherein the dissolution rate ofthe material of the distal section is substantially higher than that ofthe material of the proximal section, so as to shorten the dissolutiontime of the distal section by from one to ten minutes. This designenables the electrode of the invention to be inserted close to thetarget tissue with both matrix sections intact; upon dissolution of thematrix material of the distal section, in which a distal or second endportion of the electrode body and/or the tip section is embedded, theelectrode may be pulled back in the tissue by a short distance or pushedfurther into the tissue by a short distance.

It is within the ambit of the invention for a matrix of the invention tocomprise a dissolution enhancing means such as channels that can beinfiltrated by body fluid. Thus the matrix body or a portion thereof mayhave non-porous or a porous structure.

It is also within the ambit of the invention to provide the matrix witha means for retarding dissolution. Retardation of the dissolution of thematrix material can be achieved by arranging one or more layers ofdissolution retardation coating on the matrix body or sections thereof.The matrix dissolution retardation coating is of a material thatdissolves in an aqueous environment at a rate substantially slower thatof the matrix body or a matrix body section protected by it.

The matrix dissolution retardation coating may also be one that is notreadily dissolvable but is degradable in an aqueous environment, such asa polyester coating, for instance a polyglycolate, polylactate,poly(glycolate, lactate) or polycarbonate coating or a peptide coating,such as a coating of collagen.

According to another preferred aspect of the invention the provision ofan outer layer of a material that reduces friction in respect of thetissue during the implantation is preferred. An outer layer or coat of alow friction material may reduce injury caused by the implantationprocedure. It may also reduce the risk of carrying with it cells, suchas meningea fibroblasts, from a superficial tissue to a deeper tissueduring electrode implantation. Suitable coat materials includepolyvinylalcohol, collagen, chitin, agar, hyaluronic acid, cf U.S.Patent Application No. 2008234790 A1 incorporated herein by reference.

Drugs

According to the present invention, any drug or combination of drugs ofinterest may be administered to soft tissue via the electrode and/orarray matrix of the invention. Preferred drugs according to theinvention include drugs for treatment of bleeding, infection, andinflammation. Drugs reducing or preventing encapsulation by scarformation and preventing cell death are also preferred. According to theinvention the drug is released into the tissue adjacent to an electrodebody. According to a preferred aspect of the invention the drug isembedded in a separate biocompatible material forming a coat on anelectrode or one or several electrode bodies of an electrode bundle. Theelectrode or array matrix may be applied in one or several layers. Forinstance, only one of several layers may contain a drug or two orseveral layers of a coating may contain different drugs. By providingelectrodes coated in this manner in an electrode bundle or array ofelectrode bundles, different drugs may be released in the vicinity ofselected electrodes of the invention. Drugs may also be comprised bymicrospheres or other types of microparticles embedded in the matrix,and may be released from the microspheres and microparticles upondissolution or degradation of the matrix concurrently or subsequently.

According to a preferred aspect of the invention, different drugs arereleased from the matrix in a time-controlled manner. For example,bioactive components designed to minimize risks of bleeding, infectionand/or apoptosis may be favourable to release during an early phaseafter implantation. The matrix can in this case be designed so that therelease of the embedded compounds starts during or immediately afterimplantation. In case of drugs acting for an extended period of time itis preferred to release the drug slowly over days or weeks. To achieve along-lasting effect a gene vector may be used instead of a drug or beincluded in the matrix in addition to a drug. By combining differentrelease mechanisms it is possible to control the delay and rate ofrelease of bioactive components embedded in the matrix of the electrodeor probe. Upon introduction of the matrix into the physiologicalenvironment, the active component/s are released into the surroundingbody fluid by different mechanisms such as diffusion, swelling followedby diffusion or degradation. Any or all of these mechanisms, here termedpassive release mechanisms, might be used. The rate of passive emissionof the active ingredient is dependent on the structure of the matrix andits response to physiological parameters such as temperature, pH, ionicstrength, enzyme concentrations. Drugs to be released with a delay maybe included in separate compartments in the form of for example,microcapsules or rods inserted in parallel with the electrode, electrodebundle or array. The microspheres and microrods or microbars maycomprise a material that dissolves slower than the matrix. It is alsopossible, although not preferred, to use materials that do not dissolveafter implantation and thus, after the release of the drugs through forexample pores, remains in the tissue.

The drug of the invention may also be embedded in a separate matrixbiocompatible material for coating an electrode body. The arrangement ofseveral layers of matrix material on an electrode body, each layercontaining a different drug or a different combination of drugs is alsowithin the ambit of the invention. Thereby drugs comprised by an outermatrix layer can be released before a drug comprised by an inner matrixlayer. In certain applications it is necessary to provide sustainedrelease of a drug over one month and even over several months. A slowand/or delayed release may be particularly suitable for release ofsubstances promoting trophical tissue stimulation for enhancedtissue-electrode interaction and healing. In such case, the innermostportion of the matrix material should preferably be of low solubility inbody fluids but be biodegradable. Degradation of the coating materialcan be for making a drug slowly accessible. A slowly dissolving ordegrading matrix material will gradually release a drug. For slowrelease a drug may be chemically linked to the matrix material orsterically blocked from diffusion through a swollen matrix. The drug ofthe invention may also be part of a polymer matrix material, becomingaccessible as a bioactive monomer upon degradation of the polymer.

According to another preferred aspect of the invention the electrodematrix or array matrix is covered with a thin coating containing a drug,such as a drug counteracting possible acute detrimental effects due tothe insertion procedure, such as bleedings or microbial contaminations,the coating being released within a short time after insertion of theelectrodes into the tissue.

In a further embodiment of the invention, charged bioactive componentscan be made accessible by active release, for example by applying avoltage between the inner core of an electrode and another electrodeand/or the surrounding tissue. This will lead to electrophoresis ofcharged components contained in the coating of the electrode. This canalso be combined with charged layers to facilitate gradual migration ifdesired (U.S. Pat. No. 6,316,018). Alternatively, the release can becontrolled by the use of externally applied stimuli such as ultrasoundor electrical/magnetic fields. Uncharged bioactive components can alsobe encapsulated in dissolvable charged microcapsules that can be causedto migrate to the surface of the coating by application of a voltage.

For a drug designed to be released during heating or burning of tissue(e.g. for ablation of tissue, tumors, ligation of vessels etc.) asignificantly higher temperature threshold can be used (as compared torelease at body-temperature). Increase of temperature will changephysical properties of the coating thus allowing the diffusion of thebioactive component into the neighbouring tissue. Example of a materialhaving a such property is poly(N-isopropylacrylamide-co-acrylamide)co-polymer. The ratio between N-isopropylacrylamide and acrylamide willdetermine the temperature threshold. (Fundueanu, Acta Biomaterialia,Volume 5, Issue 1, January 2009, Pages 363-373).

Time-controlled release of bioactive components may also be controlledby specific cleavage or enzymatic degradation of certain parts of thematrix. This can be obtained by adding thin enzymatically degradablelayers encapsulating the bioactive components (Itoh et al. 2008) or byconjugating the bioactive components to other molecules requiringcleavage for release. In one embodiment of this design the bioactivemolecules are part of the matrix polymer itself, thus being released bybiologically controlled cleavage/degradation of the matrix.

Alternatively/additionally, an agent embedded in the matrix may not beinitially bioactive but can become so through a process of activation,such as by hydrolytic cleavage or enzymatic degradation. By this a drugmay be made selectively accessible in different cell- or tissue typesand in a differential time-controlled manner. For long-term therapeuticeffect gene transfer is believed to be more efficient thanpharmacological treatment, and may thus be the treatment of choice foranti-inflammatory/anti-scaring conditioning of tissue surrounding animplant. In addition to minimizing inflammatory tissue response, genetherapy offers also a possibility of experimentally altering propertiesof surrounding neurons, thereby enabling experimental manipulation on amolecular level. Inducing changes in gene expression offers furtherinteresting experimental applications when combined withelectrophysiological stimulation paradigms utilizing the implantedelectrodes.

In a case where it is desirable to administrate the drugs in preciseamounts over extended periods of time, catheters attached to a drugdelivery system may, in addition, be used for drug delivery in thetissue receiving the implant. In this case the catheters are preferablyembedded in the matrix. The catheters can have one or several holethrough which the drug solution can pass into the tissue. Several drugdelivery system operating either as implantable minipumps (intrathecalpumps: U.S. Pat. No. 5,820,589, U.S. Pat. No. 6,375,655. U.S. Pat. No.7,229,477; CNS pump: U.S. Pat. No. 7,351,239; osmotic pumps: U.S. Pat.No. 6,471,688, U.S. Pat. No. 6,632,217) or as external pumps(percutaneous pumps: U.S. Pat. No. 7,471,689, U.S. Pat. No. 6,632,217)are known in the art. The catheters can either be made of slowlydissolvable material or non-dissolvable material. It is also within theambit of the invention to combine electrodes and microdialysis orelectrodes and voltammetry to measure released bioactive molecules inthe tissue as a consequence of electrical stimulation or natural tissueactivity. i.e. neurotransmitters such as small moleculeneurotransmitters (for example acetylcholine, dopamine, serotonin,histamin, norepinephrine and epinephrine), amino acids (for exampleGABA, glycine and glutamate), neuroactive peptides (for examplebradykinin, substance P, neurotensin, endorphins, enkephalin,dynorphins, neuropeptide Y, somatostatin, cholecystokinin) and solublegases (for example nitric oxide).

Also preferred is a drug that stops minor bleedings induced by theelectrode insertion procedure, for instance a coagulation factor. Mostpreferred is factor VIII or a functional derivative thereof. Otherpreferred coagulation stimulating drugs comprise combinations of factorIX, II, VII and X; factor IX; a combination of von Willebrand factor andfactor VIII; factor Vila or human fibrinogen.

Also preferred is a drug controlling vasoconstriction, such as a drugpromoting the production of NO, in particular glyceryl nitrate or afunctional derivative thereof. In cases where there is a risk that localvasoconstriction may lead to a brain infarct due to clogging of theaffected vessel a drug against trombocyte aggregation can be used, suchas, for instance, klopidogrel, tiklopidine, acetylsalicylic acid,dipyramidol, iloprost, abciximab, eptifibatid, tirofiban. Localvasoconstriction may also be treated by a drug for inducing peripheralvasodilatation such as ergoloid mesylate.

For preventing or combating local infection a drug comprised by theelectrode or array matrix is selected from the group of antibiotics. Inselecting a proper antibiotic, the kind of bacterial strain to be foughtand its resistance pattern must be taken into account. Examples ofuseful antibiotics are doxycyklin; lymecyklin; oxitetracyklin,tetracyklin; tigecyklin; kloramfenikol; ampicillin; amoxycyklin;pivmecillinam; mecillinam; bensylpenicillin; fenoximetylpenicillin;dicloxacillin; kloxacillin; flukloxacillin; amoxicillin combined withenzyme blockers; piperacillin combined with ensyme blockers; cefalexin;cefadroxil; cefuroxim; lorakarbef; cefotaxim; ceftazidim; ceftriaxon;ceftibuten; cefepim; aztreonam; meropenem; artapenem; imipenem combinedwith enzyme blockers; trimetoprim; sulfametoxazol and trimetoprim;erytromycin; roxitromycin; klaritromycin; azitromycin; telitromycin;klindamycin; tobramycin; gentamycin; amikacin; netilmycin; ofloxacin;ciprofloxacin; norfloxacin; levofloxacin; moxifloxacin; vankomycin;teikoplanin; fusidic acid; metronidazol; tinidazol; nitrofurantoin;metenamin; linezolid; daptomycin.

Drugs according to the invention for controlling astrocytic andmicroglial responses comprise naturally occurring agents selected frominterleukins, neurokinins, transforming growth factors, epidermal growthfactors, oestrogen, neuropeptides, cannabinoids and neurotrophicfactors, and their combinations. Artificially derived agents may also beused, for instance minocycline. Interleukin and growth factorantagonists are also included to the extent that the are capable ofcontrolling glial response after insertion of an electrode, an bundle ofelectrodes or an array of bundles of electrodes of the invention intocentral nervous system tissue.

Further drugs according to the invention comprise NSAIDs,glucocorticoids, prostaglandins, and agents promoting cell adhesion.Furthermore, anti-inflammatory and immunosuppressant drugs are included,which can be used to control glial response, such as natural orsynthetic glucocorticoids, for instance dexamethasone, and certainNSAIDs such as indomethacin.

Drugs promoting the survival of neurons, such as neurotrophins and theircombinations are also comprised by the invention. Neurotrophins ofparticular interest include nerve growth factor, brain-derivedneurotrophic factor, basic fibroblast growth factor, glial-derivedneurotrophic factor, neurotrophin-3, neurotrophin-4/5, neurotrophin 6,insulin-like growth factor, epidermal growth factor, and neurturin. Alsoincluded are lazaroids, superoxide dismutase, caspase inhibitors,inhibitor of apoptosis proteins (IAPs), Bcl-2 (B-cell lymphoma 2) familymembers and flunarizine, which may promote cell survival or inhibit celldeath, apoptosis and/or necrosis of neurons after trauma or ischemia.Furthermore, tetracycline can be used as a drug with bothneuroprotective action and anti-inflammatory effect. Further usefulagent include ECM proteins (extra cellular matrix proteins, mainlyproteoglycans), tenascins, hyaluronic acid and laminin, which canpromote neurotrophic support and survival (cf. U.S. Patent ApplicationNo. 2007/0198063 and U.S. Pat. No. 5,202,120, which are incorporatedherein by reference).

The drug of the invention furthermore include agents preventing theformation of connective tissue and promoting angiogenesis, for instancevasoactive intestinal peptide (VIP) and vascular endothelial growthfactor (VEGF).

In another embodiment of the invention, cells in tissue surrounding anelectrode, a bundle of electrodes or an array of electrode bundles ofthe invention are manipulated through the delivery of genetic vectorsgiving rise to modification of gene expression and translation ofcertain proteins (Lowenstein et al., 2007; Storek et al, 2008) Thegenetic material is preferably delivered to the surrounding cells bymeans of a viral vector embedded in the coating material or encapsulatedin microspheres disposed therein. Adenoassociated viral vector systemsare known in the art, which, upon injection into the brain, will lead toexpression of the inserted gene in neighbouring neurons for at least 10months (U.S. Pat. No. 6,436,708 incorporated herein by reference). Otherviral vector systems such as Herpes simples virus (HSV), adenovirus orlentivirus based systems known to be efficient in regards of topicalgene delivery into neurons and/or glial cells are also within the ambitof the present invention. Although not particularly preferred, aretroviral vector may optionally be produced by other cells immobilizedin the matrix (cf U.S. Pat. No. 6,027,721).

For certain applications non-viral vector systems are preferred meansfor gene delivery. Such systems include, for instance, plasmid liposomecomplexes or cationic lipid systems. To facilitate transport of plasmidsinto surrounding cells using non-viral transfection systems, pulses ofelectrical current may be passes through an electrode of the inventionto effect electroporation of plasma membranes, resulting in a localizedand controlled gene transfection (Jaroszeski et al., 1999).

While the drug types mentioned above serve to reduce adverse reactionsand complications caused by soft tissue reacting against foreignimplants, drugs with other properties may also be comprised by thematrix and/or the coating of individual electrode. In one embodiment ofthe invention, a bioactive molecule considered to be a drug candidate isembedded in the matrix or the coating of a recording electrode.Embedding different bioactive molecules of this kind in the coatings ofthe electrodes of an electrode bundle allows to record electricalsignals from different neurons and thus the simultaneous screening ofmultiple drug candidates.

In another embodiment of the invention, markers used to stain oridentify neurons from which recordings are made are embedded in thecoating of the different electrodes. Such markers include fluorophores,including voltage and calcium sensitive molecules (for example Fluo3that can be used to measure calcium concentration) that are taken up byneurons or glia close to the electrode tips. Fluorophores that are noteasily released from the electrodes may be used for identification ofthe electrodes. Fluorophores may not only serve as a neuronal stain butmay also be used to measure e.g. the intracellular calcium concentrationin cells or measure the potential of the neuronal membrane. Using acombination of confocal microscopy or 2-photon microscopy withrecording/stimulation through the individual electrodes of the inventionand/or optical stimulation through embedded optical fibers it is thenpossible to identify which of the neurons are recorded/stimulated bywhich electrode in the multichannel electrode.

In one preferred embodiment of the invention the drug for incorporationinto a matrix of the invention is encapsulated in a microsphere. Such amicrosphere can range in size from a few nanometers to a tenth of amillimeter. For instance, the following microencapsulation technologiescan be used for encapsulating the drug of the invention: spray drying,spray chilling, rotary disk atomization, fluid bed coating, stationarynozzle coextrusion, centrifugal head co-extrusion, submerged nozzleco-extrusion, pan coating, phase separation, solvent evaporation,solvent extraction, interfacial polymerization, simple or complexco-acervation, in-situ polymerization, liposome technology,nanoencapsulation. For instance, the following materials can be used asthe shell building material of a microcapsule: proteins,polysaccharides, starches, waxes, fats and other natural and syntheticpolymers. An optimal release rate of the encapsulated drug can beachieved by proper selection of the material used to construct thespheres, the size of the spheres, type and amount of embedded drug andadditives incorporated in the spheres. Release rates of microspheres arecommonly of first order. However, zero order release rates can beachieved by using different methods such as providing an optimal ratioof different sized particles and depot layer techniques. Themicrospheres of the invention might themselves contain smaller spheresin which the drug is embedded. Microspheres can be designed to bedissolvable but at a slower rate than the surrounding matrix.Alternatively the microspheres can be designed to be non-dissolvable.For example, biocompatible synthetic polymers such as polyurethane(including polycarbonate urethanes), isobutylene,polystyrene-isobutylene-polystyrene, silicone (e. g., polysiloxane andsubstituted polysiloxane), a thermoplastic elastomer, an ethylene vinylacetate copolymer, a polyolefin elastomer, ethylene propylene dieneM-class rubber, polyamide elastomer, hydrogel or combinations thereofcan be used for this purpose. Such hydrogel polymers include, but arenot limited to, derivatives of 2-hydroxyethylmethacrylate, polyvinylalcohol, polyethylene oxide, polyethylene glycol, polyurethane hydrogel,naturally occurring hydrogels, e. g., gelatin, hyaluronic acid,cross-linked albumin, etc. or combinations thereof.

Method of Manufacture

According to the invention is also disclosed a method of manufacture ofan electrode body of the invention embedded in a matrix. The methodcomprises providing a fixation means, fixing the electrode body and,optionally additional elements to be imbedded, such as optical fibres,contractile elements, etc., in the fixation means in a desiredconfiguration, applying a sheath covering the thus fixed electrode bodyand accessories except for at the proximal coupling section thereof,applying a solution or suspension of a first matrix material on theelectrode in a manner so as to cover the portions of the electrodeintended to be embedded, allowing the solvent/dispersant of the matrixsolution or suspension, respectively, to evaporate or harden, removingthe sheath, and releasing the electrode from the fixation means. Forembedment of the electrode in two matrix materials so as to formcorresponding matrix compartments, each enclosing a portion of theelectrode, an appropriate portion of the electrode body fixed by afixation means as described above is coated with a solution orsuspension of the first matrix material, the solvent/dispersant of whichis subsequently evaporated, followed by coating the portion of theelectrode body remaining to be coated with a solution or suspension ofthe second matrix material, subsequently evaporating thesolvent/dispersant of the second matrix material, and releasing theelectrode from the fixation means. In the method the electrode body ispreferably disposed in a sheath of smooth material of low wettabilitysuch as a polyfluorinated hydrocarbon polymer or silicon rubber, andfixed therein. To facilitate solvent evaporation the sheath material isadvantageously porous, in particular micro-porous. After application anddrying of the matrix material(s), the electrode is withdrawn from thesheath.

An alternative method of embedding an electrode body of the inventioninto two matrix materials forming distinct matrix compartments,comprises embedding the entire electrode body in a first matrixmaterial, dissolving a portion of the first matrix material, preferablya distal portion extending from the distal end, covering the nownon-embedded distal portion of the electrode body with a second matrixmaterial by, for instance, taking recourse to a sheath applied on thenon-embedded distal portion, filling the sheath with a solution orsuspension of the second matrix material, evaporating the solvent so asto dry/harden the second matrix material, and removing the sheath.

The electrode body of the invention can be coated by using a singlecoating technique or combination of coating techniques, such as by dipcoating, spray coating, melting processes including extrusion,compression molding and injection molding or a combination of differenttechniques.

In a representative example of a stepwise procedure, the electrode bodyis first dip-coated with a suitable resorbable polymer or blend ofpolymers, in particular collagen, gelatine, polyvinyl alcohol andstarch, dissolved in a proper solvent. Other polymers can also be used.The thickness of the polymer layer is controlled in manner known to aperson skilled in the art. The coating is then subjected to a dryingstep. The dip coating and drying steps can be done once or can berepeated, depending on required thickness of the final coating. In thenext step the polymer is loaded with the drug. The electrode issubmerged into a solution containing the drug. The solvent used shouldbe one in which the polymer swells and in which the drug dissolves.After an appropriate contact time, such as from less than a second to 5min or more, the electrode is removed from the solution and the matrixdried by evaporation of the solvent, possibly under reduced pressure.

In a one-pot procedure the electrode body is submerged into a solutionof the polymer and the drug of choice in an optimal concentration for adesired coat thickness and a desired drug loading. The electrode is thenremoved from the solution and the solvent evaporated, possibly underreduced pressure.

Alternatively the coating is generated by spray coating, in which apolymer/drug solution in a suitable solvent is sprayed on the electrodebody. The thickness of the coating can be controlled by the number ofspraying and drying (evaporation) cycles and the amount of polymer anddrug in the solution.

Also comprised by the invention are hydrogel coats of partiallyhydrolyzed water-soluble polymers such as polyvinyl alcohol, polyacrylicacid and derivatives of polyacrylic acid, e.g., poly(N-isopropylacrylamide). An increase in temperature makes thesehydrogels contract, thereby forcing the drug out of the coating.Alternatively, the temperature-sensitive hydrogel is an interpenetratinghydrogel network of poly(acrylamide) and poly(acrylic acid), and theincrease in temperature causes the hydrogel to swell, thereby allowingthe drug to diffuse out of the gel.

Also comprised by the invention is the use of a polymer or a polymerblends for electrically triggered release, such as polyvinylalcohol/chitosan.

Method of Implantation

According to the invention is also disclosed a method of inserting orimplanting an electrode, an electrode bundle and an array of electrodesor electrode bundles of the invention into soft tissue.

A method of inserting or implanting a flexible medical microelectrode ofthe invention in tissue in a desired configuration comprises: providingthe electrode in the desired configuration at least partially embeddedin a substantially rigid biocompatible water soluble or biodegradablematrix comprising a drug capable of release into a body fluid; insertingor implanting the matrix embedded electrode into tissue; allowing thematrix to dissolve or to be degraded in situ. It is preferred for thematrix to comprise a proximal section of lower dissolution ordegradation rate and a distal section of higher dissolution ordegradation rate.

A method of inserting or implanting a medical microelectrode bundle ofthe invention into tissue in a desired configuration comprises:providing the electrode bundle in the desired configuration embedded ina substantially rigid biocompatible shared electrode matrix that issoluble or biodegradable in a body fluid, the shared electrode matrixcomprising a drug capable release into a body fluid; inserting orimplanting the matrix embedded electrode bundle into tissue; allowingthe shared electrode matrix to dissolve or be degraded in situ. It ispreferred for the shared electrode matrix to comprise a proximal sectionof lower dissolution or degradation rate and a distal section of higherdissolution or degradation rate.

A method of inserting or implanting an array of electrode matrixembedded medical microelectrodes or microelectrode bundles of theinvention embedded in a common array matrix into tissue in a desiredconfiguration comprises: providing an array of microelectrodes ormicroelectrode bundles in a desired configuration embedded in asubstantially rigid array matrix that is soluble or biodegradable in abody fluid, the array matrix comprising a drug capable of release into abody fluid; inserting or implanting the matrix embedded array ofmicroelectrodes or microelectrode bundles into tissue; allowing theelectrode/shared electrode matrices and the array matrix to dissolve orbe degraded in situ.

Uses

The invention also relates to the use of the matrix-embedded electrode,the matrix-embedded electrode bundle or the array of matrix-embeddedelectrode bundles for long-lasting nerve stimulation, multi-channelrecordings of electrical neuronal activity and levels of transmittersubstance through measurements of redox reactions and lesions of thetissue for scientific, medical and animal care purposes.

According to a preferred aspect of the invention the microelectrode, themicroelectrode bundle, and the array of microelectrodes ormicroelectrode bundles of the invention is used in a patient or animalfor: recording signals from neurons remaining after brain and/or spinaldamage; stimulating neurons to compensate for lost functions; providingpain relief by stimulation of analgesic brain stem centres; providingrelief or decrease of tremor and other motor symptoms in Parkinson'sdisease; relief or decrease of choreatic and other involuntary movementsby stimulation within the basal ganglia or associated nuclei; boostingmemory by stimulation of cholinergic and/or monoaminergic nuclei in caseof Alzheimer's disease or other degenerative disease; control of mood,aggression, anxiety, phobia, affect, sexual over-activity, impotence,eating disturbances by stimulation of limbic centres or other brainareas; providing rehabilitation after stroke or damage of the brainand/or spinal cord by stimulation of remaining connections in the cortexcerebri or descending motor pathways; providing re-establishment ofcontrol of spinal functions such as bladder and bowel emptying afterspinal cord injury by stimulating relevant parts of the spinal cord;providing control of spasticity by stimulation of inhibitory supraspinaldescending centres or appropriate cerebellar areas; providingre-establishment of somatosensory, auditory, visual, olfactory senses bystimulation of relevant nuclei in the spinal cord and the brain.

According to another preferred aspect of the invention themicroelectrode, the microelectrode bundle, and the array ofmicroelectrodes or microelectrode bundles of the invention is used in apatient or animal for combined monitoring and stimulation, in particularfor: monitoring of epileptic attacks by electrodes implanted into theepileptic focus coupled to a system for delivering antiepileptic drugsor electrical pulses; compensating for a lost connection in the motorsystem by recording central motor commands, followed by stimulatingexecutive parts of the motor system distal to a lesions; recordings ofblood glucose levels to control the hormone release.

According to a further preferred aspect of the invention themicroelectrode, the microelectrode bundle, and the array ofmicroelectrodes or microelectrode bundles of the invention is used in apatient or animal for locally lesioning tissue, in particular tumour orabnormally active or epileptogenic nervous tissue by passing current ofsufficient magnitude through said electrode, electrode bundle or arrayof electrode bundles.

In biomedical research, use of the microelectrode, the microelectrodebundle, and the array of microelectrodes or microelectrode bundles ofthe invention can be used for studying normal and pathological functionsof the brain and spinal cord, in particular over a long time.

In a patient having a neuroprosthetic device, the microelectrode, themicroelectrode bundle, and the array of microelectrodes ormicroelectrode bundles of the invention can be used to form an interfacebetween a nerve and said device.

In a patient or an animal, the microelectrode, the microelectrodebundle, and the array of microelectrodes or microelectrode bundles ofthe invention can be used for controlling the function of an endocrineor exocrine organ, such as in controlling hormone secretion.

In a patient or animal, the microelectrode, the microelectrode bundle,and the array of microelectrodes or microelectrode bundles of theinvention can be used for controlling the function of one or moreskeletal muscles or a heart muscle.

The invention will now be explained in more detail by reference to anumber of preferred embodiments illustrated in a rough drawingcomprising a number of figures, which are however not to scale.

DESCRIPTION OF THE FIGURES

FIG. 1a is a longitudinal section through a first embodiment of theelectrode of the invention comprising an electrode body including a tipsection and a main section of a non-conductive silk core coated withsilver and gold, a polymer insulating coat on the main section, the mainsection having a wavy configuration, the matrix not being shown;

FIGS. 1b and 1c are transverse sections A-A, B-B through the electrodebody, respectively, of the electrode of FIG. 1, the matrix element notbeing shown;

FIG. 1d is the embodiment of FIG. 1a , in an extended state, upondissolution of the matrix in a body fluid;

FIG. 2a is a longitudinal section through a second embodiment of theelectrode of the invention, in a state corresponding to that of theembodiment of FIG. 1a , the matrix element not being shown;

FIG. 2b is an enlarged partial view of the tip of the electrode of FIG.2a , the matrix element not being shown;

FIG. 3a is a longitudinal section through a third embodiment of theelectrode of the invention, in a state corresponding to that of FIG. 1a, the matrix element not being shown;

FIG. 3b is an enlarged partial view of the tip of the electrode of FIG.3a , the matrix element not being shown;

FIGS. 4a-4c are longitudinal sections through a fourth embodiment of theelectrode of the invention embedded in a dissolvable matrix (4 a), in astate after insertion into a soft tissue and after dissolution of thematrix (4 b), and in an extended state (4 c) in the tissue;

FIG. 5a is a longitudinal section through a first embodiment of a bundleof electrodes of the invention;

FIG. 5b is a transverse section C-C through the embodiment of FIG. 5 a;

FIG. 6 is a longitudinal section through a second embodiment of a bundleof electrodes of the invention embedded in a combination of dissolvablematrices, in a view corresponding to the view of the bundle ofelectrodes in FIG. 5 a;

FIG. 7a is a longitudinal section through a first embodiment of theelectrode bundle array of the invention comprising four electrodebundles of the embodiment of FIGS. 5a , 5 b;

FIG. 7b is a transverse section D-D through the electrode bundle arrayof FIG. 7 a;

FIG. 8 is a longitudinal section F-F (FIG. 8a ) through a secondembodiment of the electrode bundle array of the invention embedded in acombination of dissolvable matrices and comprising a swelling means;

FIG. 8a is a transverse section E-E (FIG. 8) through the electrodebundle array of FIG. 8;

FIGS. 8b-8f illustrate the process of consecutive dissolution of thedissolvable matrices of the array of FIGS. 8, 8 a inserted into softtissue, in the same view as in FIG. 8;

FIG. 9 is a third embodiment of the electrode bundle array of theinvention comprising an optical fibre, in a longitudinal sectioncorresponding to that of FIG. 8;

FIGS. 10-11 illustrate a fourth and a fifth embodiment of the electrodeof the invention, in views corresponding to that of FIG. 1a , the matrixelement not being shown;

FIG. 12 illustrates a sixth embodiment of the electrode of theinvention, in a longitudinal section G-G (FIG. 12a ), in a viewcorresponding to that of FIG. 1a , the matrix element not being shown;

FIG. 12a is an enlarged top view, in a proximal direction, of theelectrode of FIG. 12, the matrix element not being shown;

FIG. 13 is a longitudinal section through a third embodiment of a bundleof electrodes of the invention joined at their proximal ends by anelectrode holder disk, in a view corresponding to the view of the bundleof electrodes in FIG. 5 a;

FIG. 14 is a longitudinal section through a fourth embodiment of theelectrode bundle array of the invention comprising four electrodebundles of the kind shown in FIG. 13 mounted on an array holder disk, ina view corresponding to the view of the array of bundle of electrodes ofFIG. 7 but with a portion of the distal terminal section omitted;

FIGS. 15a-15b illustrates a fourth embodiment of a bundle of electrodesof the invention comprising a biodegradable sustained drug release rod,in views corresponding to the views of the bundle of electrodes in FIGS.5a, 5b (transverse section H-H);

FIGS. 16a-16b illustrate an embodiment of an electrode array of theinvention mounted on a base dissolvable in an aqueous body fluid, in aview corresponding to the view of the bundle of electrodes in FIG. 5 a;

FIGS. 17a-17c illustrate a further embodiment of the electrode of theinvention in an axial section and in two transverse (K-K, L-L) sections.

FIG. 18 is an axial section through a still further embodiment of theelectrode of the invention, in the same view as that of the embodimentin FIG. 17 a;

FIG. 19 illustrates an additional embodiment of the electrode of theinvention in an axial section M-M (FIG. 19a ) comprising an electrodebody made from a single metal wire that also provides for electricalconnection of the electrode body to a control unit. The electrode isshown mounted on a tissue insertion tool;

FIG. 19a is a top view of the tissue insertion tool of FIG. 19 in aproximal direction;

FIG. 20 is an about axial section through an electrode array of theinvention at a level slightly above the base plate but with the baseplate shown.

DETAILED DESCRIPTION OF THE INVENTION

The first embodiment 1 of the electrode of the invention of FIGS. 1a-1ccomprising a generally oblong electrode body (2, 3, 4) including awaveform main section 2 joined to a proximal coupling section 4 at itsfirst, proximal end and to a tip section 3 at its second, distal end,the tip section provided with a point or tip 5, which may be sharp orblunt. A blunt tip 5 has the advantage of avoiding damaging bloodvessels if disposed in a tissue rich in such vessels. The proximalcoupling section 4 is a pearl of solder connecting the electrode body 2,3, 4 at its proximal end with a thin insulated conductor for electricalconnection of the electrode body 2, 3, 4 with an electrical apparatus10. The electrical apparatus 10 may be of various kind, such as forfeeding an electric current to the electrode and/or for receivingelectrical signals from the electrode. The electrode body 2, 3, 4 isflexible but substantially not resilient. As shown in the enlargedtransversal section of FIG. 1c it consists of a core 7, an intermediatelayer 8, and a coat 9. The core 7 is a silk thread on which the thinintermediate layer 8 of chromium has been deposed by ion sputtering. Theintermediate layer 8 is covered by a coat 9 of polyvinyl formal. Incontrast to the main section 2 the tip section 3 is not insulated, thatis, lacks the coat 9 (FIG. 1 b). Applying a slight force to the oppositeends of the electrode body 2, 3, 4 so as to draw it apart results in theextended, substantially straight configuration of the electrode bodyshown in FIG. 1 d.

The second embodiment 101 of the electrode of the invention shown inFIGS. 2a, 2b differs from the first embodiment by the waveform patternof its body main section 102. Reference nos. 103, 104 refer to the tipsection, which ends in a sharp point 105, and to the electrode proximalcoupling section, respectively.

The third embodiment 201 of the electrode of the invention shown inFIGS. 3a, 3b differs from the first embodiment by a roughened surfaceportion 210 of the tip section 203 extending from the blunt tip 205 inthe direction of the wavy electrode body main section 202 and theelectrode proximal coupling section 204. The roughening improvesretention at the implantation site and increases the contact area of theelectrode with surrounding cells, thereby lowering the electricalresistance between the electrode and the cells.

In FIG. 4a a fourth embodiment 321 of the electrode of the invention isshown with its tip section 303 and its body main section 302 embedded ina matrix shell 312 of water soluble material in a manner so that thesharp electrode tip 305 points in the same direction as the blunt matrixshell tip 313. At a distance from the tip 305 a barb 314 extends in askew proximal direction from the tip section 303. Except for at itsconductor lead 306 bearing proximal coupling section 304 the electrodemain and tip sections 202, 203 are fully embedded in the matrix shell312. The embedded electrode body main section 302 has a zigzagconfiguration. The combination 321 of electrode tip 303 and main 301sections, at the one hand, and the matrix shell 312, on the other, is aconformationally stabilized electrode. In this stabilized form 321 theelectrode can be inserted into soft tissue while retaining the zigzagconfiguration of its body main section 203. Within a short time uponinsertion the matrix shell 312 is dissolved by body fluid (FIG. 4b );the electrode main section does 203 substantially retain the zigzagconfiguration in which it had been embedded in the matrix shell 312 andin which it had been inserted into the tissue. By the barb 314 thecombination 301 including electrode tip and main sections 202, 203 isanchored in the tissue, in particular against a force seeking towithdraw it. By application of a withdrawing force to the proximalcoupling section 304 the electrode body main section 302 isstraightened, viz. extended, so as to assume the straightenedconfiguration 302′ shown in FIG. 4c . In an exemplary embodiment of theinvention, the matrix shell 312 is sodium hyaluronate comprising theserotonin antagonist (5-HT₃ antagonist) ondansetron (12% by weight)dispersed therein.

A first embodiment of a matrix-embedded bundle 411 of four electrodebodies of the invention is shown in FIGS. 5a, 5b . The electrode bodies402 a, 403 a; 402 x, 403 c, which are of same kind as that 101 of FIGS.2a, 2b , are disposed in parallel and equidistantly from the rotationalaxis S of the bundle 411 in a dissolvable matrix body 412 of sodiumhyaluronate comprising a 0.05% (w/w) solid solution of ondansetron, aserotonin (5-HT₃) antagonist. In respect of the electrode body 402 a ofthe first electrode, the bodies 402 b, 402 c, 402 d of the otherelectrodes are disposed in an angle of 90°, 180° and 240°, respectively.In FIG. 5a the tip sections 403 a, 403 c and the proximal couplingsections 404 a, 404 c of the first and third electrodes, respectively,are also shown. The generally cylindrically tapering matrix body 412tapers in a distal direction, only slightly at start but more pronouncedtowards its distal pointed end 413.

The second embodiment of a matrix-embedded electrode bundle 511 of fourelectrode bodies of the invention shown in FIG. 6 comprises fourelectrode bodies 502 a, 502 b of the kind disclosed in FIGS. 2a, 2b andin the same disposition in respect of a rotational axis S′ as in thematrix-embedded electrode bundle 411 of FIGS. 5a, 5b . In contrast tothe embodiment of FIGS. 5a, 5b the matrix body comprises two sections, aproximal section 512′ enclosing the electrode bodies' main sections 502a, 502 c, etc., and a distal section 512″ enclosing the tip sections 503a, 503 c. The dissolution rate of the proximal matrix body section 512′is slower than that of the distal matrix body section 512″. This allows,for instance, insertion of the entire matrix-embedded bundle 511 to adesired first depth or level of a soft tissue and, upon dissolution ofthe distal section 512″ further insertion of the bundle 511 having lostits distal section 512″ to a second depth or level, during which the nolonger matrix embedded tip sections 503 a, 503 c may bend, for instancebend away from the central axis S′. In an exemplary embodiment of theinvention, the proximal matrix body section 512′ consists ofgelatine/lactose (9:1, w/w), whereas the distal body section 512″consists of mannose comprising 5% by weight of gelatin and 0.01% byweight of factor VIII.

A distally pointed 631 array 620 of electrode bundles of the inventioncomprises four matrix-embedded electrode bundles disposed equidistantlyand rotationally symmetrically (four-fold rotational symmetry) from anarray axis R of the invention (FIGS. 7a, 7b ). The array 620 comprisesfour electrode bundles of the kind illustrated in FIGS. 5a, 5b , ofwhich only the main body sections 602 a-602 d of the first bundle areidentified by reference numbers. The electrode bundles are embedded insolid dissolvable electrode matrices 612 a-612 d of same kind,respectively, comprising polyglycolic acid microspheres 619 containing10% by weight of metoprolol succinate dispersed therein. The fourmatrix-embedded electrode bundles are disposed in parallel with theirmatrix tips 613 a, 613 c pointing in the same, distal direction. Thematrix-embedded electrode bundles are joined by an array matrix 630 of a2:1 (w/w) mixture of galactose and agarose, which is dissolvable in anaqueous environment. The array matrix 630 is preferably different incomposition and dissolution or swelling rate from the material of theelectrode matrices 612 a-612 d. The material of the embedding matrices,that is, electrode and array matrices, may be one and the same but it isalso conceivable to use material(s) with different dissolution orswelling rates for one or more of them. The array 620 is provided with afemale coupling member 640 disposed centrally in the array matrix 630 atits proximal flat end face. The coupling member 640 is designed toreleasingly receive a manipulation rod 641 for insertion of the array620 into tissue.

Another projectile formed pointed 731 electrode bundle array 720 of theinvention of same symmetry as the array of FIGS. 7a, 7b is shown inFIGS. 8, 8 a. In addition to the water soluble array matrix 730connecting the electrode bundles of the array 720, the array comprises aswelling plug 750 disposed centrally in respect of the array axis T andextending from there in a radial direction to the innermost wallsections of the matrix bodies 712 a-d of polyvinylpyrrolidone comprising2% by weight of bromperidol in d,l-polylactic acid microspheres 719 (EP669 128 B1), each matrix body 712 a-d further comprising amatrix-embedded electrode bundle with four electrodes each, eachelectrode having an extendable electrode body 702 a-d, etc., whereas, inan axial direction the proximal and distal faces of the plug 750 abutthe array matrix or glue 730 by which the four matrix-embedded electrodebundles are kept in place. An insertion rod 741 is embedded in thecentral proximal portion of the array matrix 730. FIGS. 8b-8f illustratethe fate of the array 720 after insertion into soft tissue 760. FIG. 8bshows the situation immediately upon insertion of the array 720 into thetissue 760. The array 720 is still intact. FIG. 8b shows the situationabout 2 minutes upon insertion during which period the matrix array 730has dissolved in the aqueous environment of the tissue 760. Referencenumber 760 represents both soft tissue and fluid formed by dissolutionof the glue 730. The matrix bodies 712 a-d are now separated, except fora possible adhesion to the swelling plug 750 of agarose. Next theswelling plug 750, now in contact with tissue fluid, begins to swell.The situation after considerable swelling of the plug 750 is shown inFIG. 8d . The swelling plug 750 is of a material that first swells andlater dissolves in contact with aqueous body fluids. It is, forinstance, made of agarose or gelatin. The swelling of the plug makes thematrix-embedded electrode bundles move radially apart, the result ofwhich is shown in FIG. 8e . Finally, the matrix bodies 712 a-712 d areslowly dissolving in body fluid, which results in the main body sections702 a, 702 c of the electrode bodies of the first electrode bundle, themain body sections 702 a″, 702 c″ of the electrode bodies of the thirdelectrode bundle, and the main body sections of the electrode bodies ofthe other electrode bundles becoming disposed in the tissue, as shown inFIG. 8f . Contact with body fluid makes the microspheres 719 leak anaqueous solution of bromperidol intended to affect neurons (not shown)in proximity of the electrodes. By incorporating a different number ofmicrospheres 719 in each matrix 712 a-d, the amount of aqueousbromperidol leaked from microspheres 719 pertaining the respectivematrix body, thus to the respective electrode bundle, can be controlled.This can be used for studying the effect of varying concentrations of asubstance on neurons in a single experiment. To obtain an essentiallysimilar effect, one could incorporate microsphere batches of same weightbut differing in their content of bromoperidol into each of the matrices721 a-d. Alternatively, one could incorporate into each of the matrixbodies 712 a-d a different drug comprised by the same kind and amount ofmicrospheres; this would allow the comparison of the effect of differentdrugs on neurons in a single experiment.

The third embodiment of the electrode bundle of the invention shown inFIG. 13 comprises four longitudinally extendible electrode main bodysections 802 a, 802 c attached to proximal coupling sections 804 a, 804c. The bundle is embedded in a dissolvable matrix 812 narrowing towardsits distal tip 813. The proximal coupling sections 804 a, 804 c aremoulded in an electrode holder disk 807 from which their rear portionsprovided with conductors 806 a, 806 c extend. The electrode holder disk807 is made of a non-conducting polymer material. This embodiment allowsto keep the proximal portions of the electrode main body sections at adesired distance from each other, whereas their distal portions can movemore freely in respect of each other. The matrix body 812 of agarosecomprises 10% by weight of particulate levodopa 819 dispersed therein.

A third embodiment of the electrode bundle array of the invention isshown in FIG. 9. The electrode bundle array 920 comprises fourmatrix-embedded electrode bundles of which only two are shown. Itdiffers from the electrode bundle array 620 of FIGS. 7a, 7b in thatelectrodes of the invention with tip sections 903 a, 903 c of varyinglength and electrode body main sections 902 a, 902 c of same length arecomprised by a first electrode bundle embedded in a first electrodebundle matrix body 912 a, whereas a third electrode bundle embedded in athird electrode bundle matrix body 912 c comprises an electrode of theinvention comprising an electrode main body section 902 c″ and anoptical fibre 970 disposed in parallel with the electrode. The agaroseelectrode matrix bodies 912 a, 912 c comprise sustained-releasepoly(lactide-co-glycolide) microcapsules 919 containing about 2% byweight of leuprolide (U.S. Pat. No. 4,954,298). The electrode body mainsections 902 a, 902 c, 902 c″ of the array are connected via thinflexible conductors 906 a, 906 c, 906 c″ to a control unit 960 by whichthey may be powered or to which they may transmit electrical nervesignals. The optical fibre 970 is shown connected to the central unitwhich may comprise a light source for sending radiation through thefibre into the tissue in which the fibre 970 is implanted or which maycomprise means for detecting radiation emanating from the tissuereceived via the fibre 970.

FIGS. 10-12 illustrate further preferred embodiments of the electrodebody of the invention with modified tip sections.

The electrode body 1001 of FIG. 10 comprises an extendable oblongelectrode body main section 1002 and a tip section 1003 from which shorttags 1011-1011′″ extend radially/distally and spaced along the tipsection 1003.

The electrode body 1101 of FIG. 11 comprises an extendable oblongelectrode body main section 1102 and a tip section 1103 from whichdoubly curved tags 1111-1111″″ extend about radially and spaced alongthe tip section 1103.

The electrode 1201 body of FIGS. 12, 12 a comprises an non-extendablestraight electrode body main section 1202 and a tip section 1203 from aradial plane of which twenty-four rearwards curved tags, of which onlythe first and the twelfth tag 1211-01, 1211-13 extend in anumbrella-like configuration.

The electrode bundle array 1320 of the invention of FIG. 14 comprisesfour electrode bundles of the kind shown in FIG. 13. In the sectionalview of FIG. 14 only two of them can be seen. Except for matrix bodies1312 a, 1312 c and electrode holder disks 1307, 1307″ only the elementsof the first bundle, which comprises four electrode bodies, are providedwith reference numbers. Only two of the electrodes of the first bundleare visible in the figure, the first electrode comprising an electrodebody main section 1302 a and the third electrode comprising an electrodebody main section 1302 c. The electrode bodies are embedded in adissolvable, substantially conical array matrix 1312 a that narrowstowards its distal tip. Their electrode proximal coupling sections 1304a, 1304 c are moulded in an electrode holder disk 1307 of anon-conducting polymer material. The holder disks 1307, 1307″ areadhesively mounted (not shown) on an array holder disk 1335 with theirproximal faces abutting the distal face of the array holder disk 1335.To allow the leads 1306 a, 1306 c of the electrodes to pass through thearray holder disk 1335 the latter is provided with through bores 1337 a,1337 c facing the electrode proximal coupling sections 1304 a, 1304 c.The electrode bundles are disposed symmetrically in respect to andequidistantly from the array long axis (not shown). Their spacing allowsa central cylindrical portion 1336 extending in a distal direction fromthe distal face of the array holder disk 1335 to be disposed betweenthem. A central bore in the proximal face of the cylindrical portion1336 is arranged for releaseably holding a manipulation rod 1341 bywhich the array 1320 can be inserted into soft tissue. The remaininginterstice between the electrode bundles is filled with a biocompatiblematrix glue 1330 that is soluble in an aqueous environment. The matrixbodies 1312 a, 1312 c are of xanthane gum containing 8% by weight ofEudragit S100/insulin microspheres (Jain D et al., Eudragit S100entrapped insulin microspheres for oral delivery. AAPS Pharm Sci Tech 6(2005) E100-E107).

The fourth embodiment 1411 of the electrode bundle of the inventionshown in FIGS. 15a, 15b comprises four electrodes bodies 1402 a, 1403 a;1402 c, 1403 c attached to proximal coupling sections 1404 a, 1404 c.The electrode bodies are embedded in a dissolvable matrix body 1412narrowing towards its distal tip 1413. Centrally in the matrix body 1412of alginate is disposed a rod 1419 of carrageenan comprising 5% byweight of fentanyl citrate extending in an axial direction somewhatfurther than the electrode tips 1403 a, 1403 c. The electrode proximalcoupling sections 1404 a, 1404 c are moulded in an electrode holder diskfrom which their rear portions provided with conductors extend. Upondissolution of the matrix body 1412 the rod 1419 is contacted by bodyfluid, resulting in the electrode tip region being immersed in afenantyl solution.

The array 1511 of four electrodes of the invention shown in FIGS.16a-16b comprises a proximal flat base 1507, which is dissolvable in anaqueous body fluid. Four electrodes (electrode bodies 1502 a-d;electrode matrix bodies 1512 a-d) are mounted at the base 1507. Proximalcoupling sections 1502 a-d penetrate the base 1507 to allow theirelectrical connection at the rear (proximal) face via flexibleconductors to a control unit (not shown), whereas the four electrodematrix bodies extend in a distal direction from the distal face of thebase 1507, and are enclosed in array matrix element 1530, which isdissolvable in a body fluid. Particulate ciclosporin 1519 (0.1 mg perelectrode, 2-5 μm (95%)) is evenly distributed in each of the electrodematrices 1512 a-d of carboxymethyl cellulose (MW 20,000-40,000)/albumin9:1 (w/w).

A further embodiment 81 of the electrode of the invention is shown inFIGS. 17a-c . Over most of its length the straight, non-extendableelectrode body 82 of copper 87 covered by a thin coat 88 of gold isinsulated by a lacquer 89. Only a distal terminal portion 83 including asharp electrode tip 85 is not insulated. At a solder point 84 disposedat its proximal end the electrode body 83 is connected to a control unit10 via a thin flexible copper wire 86. The electrode body 83 isenclosed, except at the solder point 84, by a glucose/sodium hyaluronategelatin matrix element 90 (95:5, w/w) in which particulate nifedipine(0.05 mg per electrode, 5-10 μm (90%)) is evenly distributed.

A still further embodiment 1681 of the electrode of the invention isshown in FIG. 18. Over most of its length the straight, non-extendableelectrode body 1682 of silver covered by a thin coat 1688 of platinum isinsulated by a thin coat of polyamide 1689; except for other materialsbeing used the design of the electrode body 1682 corresponds to that ofFIGS. 17a-17c . Again, only a distal terminal portion 1683 including asharp electrode tip 1685 is not insulated. At a solder point 1684disposed at its proximal end the electrode body 1683 is connected to acontrol unit 10 via a thin flexible copper wire 1686. The electrode body1683 is enclosed, except at the solder point 1684, by a firstglucose/sodium hyaluronate matrix body 1690 (95:5, w/w) in whichparticulate nifedipine (0.05 mg per electrode, 5-10 μm (90%)) is evenlydistributed. The first glucose/gelatin matrix 1690 is covered, in turn,by a second glucose/sodium hyaluronate matrix 1693 of same compositionexcept for that it comprises, instead of nifedipine, 0.1 mg of humanheparin. The second glucose/sodium hyaluronate matrix layer 1693 iscoated with a thin layer 1692 of low-molecular weight carboxymethylcellulose comprising 10-15 i.u. of hyaluronidase.

An additional embodiment 1721 of the electrode of the invention is shownin FIG. 19. The extendable electrode body of gold-plated silverconsisting of a tip section 1703 ending in a hook 1714 and a main bodysection 1702 is embedded in a matrix body 1712 of glucose/low molecularweight polyvinylpyrrolidone 8:2 (w/w), in which starch microcapsules1719 containing 10% by weight of sodium pyruvate are distributed. Theelectrode body 1702, 1703 is fully embedded in the matrix body 1712, andis integral with a flexible electric conductor 1706 of same material anddiameter. The conductor 1706 and the electrode body 1702, 1703 is madefrom a single gold-plated silver wire insulated by a thin coat ofpolyamide (not shown), which is removed from the tip section 1703 afterthe electrode body has been given its zig-zag shape. Finally the tipsection 1703 is been bent to form the hook 1714. The nominal lengthl_(n) of the electrode body 1702, 1703 is defined by the length of theshaped wire embedded in the matrix body 1712. The matrix body 1712 hasthe form of a projectile with a flat rear (proximal) face and a bluntdistal tip 1713. The rear face of the matrix body 1712 is provided withtwo bores 1710 for insertion of coupling pins 1731 extending from anabout hemicircular support element 1732 of an electrode insertion tool1730. From the opposite face of the support element 1732A extends in theopposite direction a manipulating rod 1733 for handing by the personperforming insertion of the electrode into tissue. The electrode body1702, 1703 is coupled to an electrode control unit 10 via the flexibleconductor 1706.

An embodiment of the array 1800 of electrodes of the invention isillustrated in FIG. 20. The array comprises a base plate 1808 ofpoly(lactide-co-glycolide) in which electrode bodies 1809 of theinvention are secured at their second ends. Insulated thin gold wires1804, which are electrically connected with their rear ends of theelectrode bodies 1809, are assembled in a shielded lead 1806. The lead1806 is electrically connected with a microprocessor control unit (notshown). A short rear end portion of the electrode bodies 1809 extendsout of the respective electrode matrices 1801, 1802, 1803. Allaforementioned elements are enclosed in a carbohydrate array matrix body1810 of a matrix material designed to dissolve within a couple ofminutes in contact with soft tissue. Of the entire array 1810 is onlythe lead 1806 that extends out of the matrix body. The matrix body 1804is about bomb-shell shaped with a central axis R-R and has a blunt tip1805 and a flat rear face 1811. Upon insertion of the array 1800 intosoft tissue in an axial direction with the tip 1805 foremost the arraymatrix dissolves quickly. The electrodes with their matrices 1801, 1802,1803 are now extending like hairs of a brush about perpendicularly fromthe base plate 1808. Except for the rear end portion of their electrodebodies extending out of the respective matrices the electrodes of thearray 1800 correspond to the electrode of FIG. 17a . The adjacent tissue(not shown), which is now abutting the tips of the matrices 1801, 1802,1803, is easily penetrated by them when displaced towards the tissue bythe person carrying out the insertion of the array. This displacement issubstantially in a direction perpendicular to the direction of insertionof the array in its original state. It can be carried out bymanipulating the base plate 1808 by an array insertion instrument (notshown) that is releaseably coupled with the plate 1808 and allows todisplace the plate 1808 in both directions, that is in directionsperpendicular to each other. The matrices 1801, 1802, 1803 comprise adrug, which is released during their slow dissolution in the tissue. Thedissolution process also establishes electric contact of the electrodeswith the tissue and allows the registration of, for instance, nervesignals affected by the released drug.

An array of electrode bundles (not shown) can be designed in a similarmanner, the electrodes of FIG. 20 being substituted by electrodebundles, and can be manipulated correspondingly.

An array of electrode bundles (not shown) can be designed in a similarmanner, the electrodes of FIG. 20 being substituted by electrodebundles, and can be manipulated correspondingly.

Manufacture of the Drug-Releasing Medical Electrode, Electrode Bundleand Electrode Bundle Array of the Invention

Below, first the manufacture of individual components of thedrug-releasing medical electrode, the electrode bundle and the electrodebundle array of the invention is described, then their assemblage to thedrug-releasing medical electrode, the electrode bundle and the electrodebundle array of the invention.

Electrode Coating

The following general procedures describes the generation of a rapid tomedium release coating on an electrode. A coating of an electrode(described above) can be accomplished by using a single technique orcombinations of techniques exemplified by but not limited to dipcoating, spray coating, melting processes including extrusion,compression molding and injection molding or a combination of differenttechniques.

In a illustrative example of a stepwise procedure, the electrode isfirst dip-coated with a suitable resorbable polymer or blend of polymersfrom the listed polymers above especially collagen, gelatine, polyvinylalcohol and starch dissolved in a proper solvent.

Polymers can also be used. The thickness of the polymer layer isthoroughly controlled in ways known for those skilled in the art. Thecoating is then subjected to a drying step. The dip coating and dryingsteps could be done once or repeatedly depending on required thicknessof the final coating. In the next step the drug is loaded into thepolymer. The electrode is submerged into a solution containing the drug.The solvent should resorb the polymer as well as dissolving the drug.After an optimum time the electrode is removed from the solution and thematrix is dried. In a one pot procedure the electrode is submerged intoa solution containing a suitable polymer and a drug of choose in aconcentration optimum for a required matrix thickness and drug loading.The electrode is removed from the solution and then dried. The coatingcould also be generated by spray coating where the polymer/drug solutionis sprayed on the electrode. The thickness of the coating may becontrolled by the number of spraying and drying cycles and the amount ofpolymer and additive in the solution.

Electrodes for Temperature and Electrically Induced Release

The above mentioned methods are applicable for these applications usinga proper polymer or polymer blend with optional additives and a drug ofchoose. Examples of polymers or polymer blends with optional additivesare for temperature control: fully or intermediately hydrolyzedwater-soluble resins such as polyvinyl alcohol. Polyacrylic acid orderivative thereof, e.g., poly (N-isopropylacrylamide) gel, and theincrease in temperature causes the hydrogel to contract, thereby forcingthe drug out of the coating. Alternatively, the temperature-sensitivehydrogel is an interpenetrating hydrogel network of poly(acrylamide) andpoly(acrylic acid), and the increase in temperature causes the hydrogelto swell, thereby allowing the drug to diffuse out of the gel.(Dinarvand et al. 1995; WO 2005/067896; U.S. Pat. No. 7,066,904).Examples of polymers or polymer blends with optional additives are forelectrically triggered release: polyvinyl alcohol/Chitosan (Seon JeongKim et al., 2002. J Appl Polymer Sci), polyvinyl alcohol/poly acrylicacid (Li L et al. 2005. Nanotechnology 16, 2852-2860),

Microencapsulation of Drugs

In one preferred embodiment of the invention the bioactive componentsare encapsulated in microspheres. Microspheres can range in size fromfew nanometers to millimeters in diameter. The followingmicroencapsulation technologies can be used but not limited to inobtaining microspheres: spray drying, spray chilling, rotary diskatomization, fluid bed coating, stationary nozzle coextrusion,centrifugal head coextrusion, submerged nozzle coextrusion, pan coating,phase separation, solvent evaporation, solvent extraction, interfacialpolymerization, coacervation, in-situ polymerization, liposometechnology, nanoencapsulation. Standard methods for the manufacture ofmicrospheres are given in: Microencapsulation: Methods and IndustrialApplications. S Benita 1996 ISBN-10: 0824797035, which is incorporatedherein by reference.

The following shell-building materials are particularly useful forproducing microcapsules: proteins, polysaccharides, starches, waxes,fats, other natural and synthetic polymers. Optionally, the one or moreadditives to the shell building materials can be used to increase ordecrease the drug release rate from the microcapsules. An optimalrelease rate of the encapsulated drug can be achieved by the selectionof the shell material, the size of the spheres, type and amount ofembedded drug and additives incorporated in the spheres. The drugrelease rate of microspheres is commonly of first order. However,microcapsules exhibiting zero order release rates are also known in theart. A microsphere of the invention may contain smaller spheres in whichthe drug is embedded. Spheres can be designed to be dissolvable usingthe materials listed for the matrix above but with a slowerdissolvability than the surrounding matrix. Alternatively the spherescan be designed to be non-dissolvable using more biostable materials.For example, biocompatible synthetic polymers such as polyurethane(including polycarbonate urethanes), isobutylene,polystyrene-isobutylene-polystyrene, silicone (e. g., polysiloxane andsubstituted polysiloxane), a thermoplastic elastomer, ethylene vinylacetate copolymer, a polyolefin elastomer, EPDM ethylene-propyleneterpolymer rubber, polyamide elastomer, hydrogel or combinations thereof(WO 2005/082430). Such hydrogel polymers include, but are not limitedto, derivatives of 2-hydroxyethylmethacrylate, polyvinyl alcohol,polyethylene oxide, polyethylene glycol, polyurethane hydrogel,naturally occurring hydrogels, e. g., gelatin, hyaluronic acid,cross-linked albumin, etc. or combinations thereof. (WO 2005/082430).

For instance, when microencapsulation is conducted by an in-water dryingmethod, said w/o emulsion is further added to another aqueous phase(hereafter referred to as an external aqueous phase) to yield a w/o/wemulsion, followed by removing an organic solvent in an oil phase, toyield microcapsules. An emulsifier may be added to the above-describedexternal aqueous phase. Any pharmaceutically acceptable emulsifier canbe used, as long as it generally produces a stable w/o/w emulsion.Examples of such emulsifiers include anionic surfactants (e.g., sodiumoleate, sodium stearate, sodium lauryl sulfate), nonionic surfactants(e.g., Tween 80, Tween 60, HCO-60, HCO-70), polyvinyl alcohol,polyvinylpyrrolidone and gelatin. Two or more of these emulsifiers maybe used in combination in an appropriate ratio. The emulsifierconcentration in an external aqueous phase ranges for instance fromabout 0.01 to about 20%, preferably from about 0.05 to about 10%.

Removal of an organic solvent from microcapsules can be achieved byknown methods, including the method in which the solvent is removedunder normal or gradually reduced pressure during stirring using apropeller stirrer, magnetic stirrer or the like, and the method in whichthe solvent is removed while the degree of vacuum and temperature areadjusted using a rotary evaporator or the like.

The thus-obtained microcapsules are centrifuged or filtered to separatethem, and subsequently washed with distilled water several timesrepeatedly to remove the free physiologically active substance,drug-retaining substance, emulsifier etc. adhering to the microcapsulesurface. Then, washed microcapsules are dried under reduced pressure orfreeze-dried after re-dispersion in distilled water to further remove anorganic solvent.

For producing microspheres by a phase separation method, a coacervatingagent is gradually added to a w/o emulsion while the emulsion isstirred, to precipitate and solidify a polymer of lactic acid. Anypharmaceutically acceptable coacervation agent can be used, inparticular a mineral or vegetable oil miscible with the polymer solventand which does not dissolve the polymer used for encapsulation. Examplesof such coacervation agents include silicone oil, sesame oil, soybeanoil, corn oil, cotton seed oil, coconut oil, linseed oil, mineral oil,n-hexane and n-heptane. Two or more of these may be used in combination.The amount of the coacervation agent used is, for instance, about 0.01to about 1,000 times by volume, preferably about 0.1 to about 200 timesby volume, relative to a w/o emulsion. The thus-obtained microspheresare centrifuged or filtered to separate them, after which they arerepeatedly washed with a wash such as hexane and heptane to remove thecoacervating agent. Then the wash is evaporated by heating ordecompression.

If necessary, in the same manner as with the above-described in-waterdrying method, a free physiologically active substance and an organicsolvent are removed.

For producing microcapsules by a spray drying method, a w/o emulsion ora w/o/w emulsion produced in the same manner as in an in-water dryingmethod is sprayed by a nozzle into the drying chamber of a spray drierto volatilize an organic solvent and water in the fine droplets in avery short time so as to yield microcapsules. Examples of the nozzleinclude, for instance, a two-fluid nozzle type, a pressure nozzle typeand a rotary disc type. If necessary, microcapsules thus obtained arewashed with distilled water several times repeatedly to remove a freephysiologically active substance, a drug-retaining substance, anemulsifier, etc. adhering to the microcapsule surface. Then, washedmicrocapsules may be dried under reduced pressure or freeze-dried afterredispersion in distilled water to further remove an organic solvent.

Also, when a physiologically active substance dissolves 1) in an oilphase consisting of one hydrophobic organic solvent (e.g.,dichloromethane, chloroform, dichloroethane, carbon tetrachloride, ethylacetate, cyclohexane) and at least one hydrophobic organic solvent(e.g., methanol, ethanol, acetonitrile), or 2) in an oil phaseconsisting of a polymer solution in a hydrophobic organic solvent, or 3)in an oil phase prepared by adding at least one surfactant (e.g.,glycerol fatty acid ester, propylene glycol fatty acid ester, sucrosefatty acid ester) to the above-described hydrophobic organic solvent;these oil phases may be dispersed in an external aqueous phase used inthe above-described in-water drying method to yield an o/w emulsion,followed by removing an organic solvent in the oil phase in the samemanner as in the above-described in-water drying method, to yieldmicrocapsules. Further, this o/w emulsion can be subjected to theabove-described phase separation method or spray drying method toprepare microcapsules.

The sustained-release preparation of the present invention preferablycomprises an excipient. The excipient is desired to be low in toxicitywhen administered to a living body; be easy to dry by freeze-drying orspray-drying; and dissolve rapidly when administered to a living body ordissolve at the time of use. Examples of such excipient includes, forinstance, sugars, cellulose derivatives, amino acids, proteins,polyacrylic acid derivatives, organic salts and inorganic salts. Two ormore of these excipients may be used in combination in an appropriateratio.

Dissolvable or Degradable Bars Containing Drugs

Bars or rods of drug-conjugation material may be fabricated bydispensing a drug on a sheet-formed material dissolvable in a body fluidand then cover the drug with a material of same kind. Alternatively, adrug may be applied on a surface of a coating material followed bycovering the drug layer with the same kind of coating material. TheS-layer sheet is then cut into thin straps. One or more straps aredisposed parallel with an electrode of the invention prior to enclosingthe electrode and the straps with matrix material. Similarly, stiff rodsof a material dissolvable in a body fluid or a biodegradable materialcomprising a drug can be formed separately and enclosed in a matrixmaterial in combination with and adjacent to an electrode of theinvention. Suitable rod materials are for example, syntheticbiocompatible polymers such as, for example, polyurethane (includingpolycarbonate urethanes), isobutylene,polystyrene-isobutylene-polystyrene, silicone (e. g., polysiloxane andsubstituted polysiloxane), a thermoplastic elastomer, an ethylene vinylacetate copolymer, a polyolefin elastomer, EPDM ethylene-propyleneterpolymer rubber, polyamide elastomer, hydrogel or combinations thereof(WO 2005082430). Such hydrogel polymers include, but are not limited to,derivatives of 2-hydroxyethylmethacrylate, polyvinyl alcohol,polyethylene oxide, polyethylene glycol, polyurethane hydrogel,naturally occurring hydrogels, e. g., gelatin, hyaluronic acid,cross-linked albumin, etc. or combinations thereof. (WO 2005082430).Alternatively an electrode that is only partially insulated such asbeing covered by an insulating material only proximally or that consistsof multiple sites that are not insulated can be used to control therelease of drugs.

The bars or rods are preferably introduced into the middle of theelectrode bundle. Other locations within the electrode are alsopossible. The bars may be attached to individual electrodes to followtheir course during the unfolding process. In this case, the bars needto be relatively flexible and should have a diameter similar to that ofthe individual electrode, although other dimensions are also possible.Bars may also be relatively stiff in cases where it is desirable to letthe bars follow the main track line during insertion and drugs will thenonly be released from the cord of each electrode or electrode bundle.The bars may in this case serve a dual role of releasing drugs andadding to the stiffness of the entire electrode ensemble duringimplantation.

Embedding Electrodes and Drugs in a Matrix

Drugs can be incorporated into a matrix or a matrix compartment byblending the drugs with the materials used to build the matrix or matrixsub-compartment, and/or by blending microspheres with the matrixmaterials or matrix compartment material. Also, ready-made bars or rodsof a biodegradable material or material dissolvable in a body fluidcontaining a drug can be inserted in parallel with the electrodes. Theelectrodes can be coated with one or more layers of drug containingmatrix material and/or drug containing matrix sub-compartment material.By choice of different materials for matrix compartments different drugrelease rates can be obtained. The combination of different matrix ormatrix sub-compartment layers, drug-containing microspheres and barsshould be stable, i.e. outer layers should not in any aspect affect theinner layers/structures prior to implantation. The electrode orelectrode bundle or electrode bundle array of the invention is disposedin a sheath of a smooth material of low wettability such as apolyfluorinated hydrocarbon polymer or silicon rubber, and fixedtherein. The sheath thus functions as a mould. To facilitate solventevaporation the sheath material is advantageously porous, in particularmicro-porous. After adding the matrix or matrix compartment materialcomprising the drug, optionally a microencapsulated form into the sheathand drying (evaporating the solvent, optionally under reduced pressure),the product is withdrawn from the sheath.

The sheath can have the same form as the final probe but may also be ofsmaller size in case more material is subsequently added to the probe bydip coating or spray coating. To facilitate handling of the electrodesor other components such as bars containing drugs, optical fibers orbimetal, a micromanipulator attached to the components by a dissolvableglue is used to insert them into the mould. Moreover, the individualelectrodes may preferably be arranged in specified pattern and thenspray coated or dip coated to become fixated to each other before beingsubmerged into the matrix. The material used to fixate the electrodes orother components in a certain configuration is preferably made of thesame dissolvable materials as that constituting the matrix. The methodcomprises the manufacture of a matrix material containing drugs ofchoice and/or microspheres. This can be accomplished by simplydissolving the drugs or microspheres in the material used to produce acertain matrix compartment.

In addition, the method comprises providing a fixation means, fixing theelectrodes and bars containing drugs, and optionally additional elementsto be imbedded, such as optical fibres, contractile elements, etc., inthe fixation means in a desired configuration as described above,applying a sheath covering the thus fixed elements except for at theproximal coupling section thereof, applying a solution or suspension ofa first matrix material on the electrode in a manner so as to cover theportions of the elements intended to be embedded, allowing thesolvent/dispersant of the matrix solution or suspension, respectively,to evaporate or harden, removing the sheath, and releasing the elementsfrom the fixation means. For embedment of the electrodes and otherelements in two matrix materials so as to form corresponding matrixcompartments, each enclosing a portion of the electrode, an appropriateportion of the electrode fixed by a fixation means as described above iscoated with a solution or suspension of the first matrix material, thesolvent/dispersant of which is subsequently evaporated, followed bycoating the portion of the electrode remaining to be coated with asolution or suspension of the second matrix material, subsequentlyevaporating the solvent/dispersant of the second matrix material, andreleasing the electrode from the fixation means.

An alternative method of embedding an electrode of the invention intotwo matrix materials forming distinct matrix compartments into whichportions of the electrode are embedded, comprises embedding the entireelectrode in a first matrix material, dissolving a portion of the firstmatrix material, preferably a distal portion extending from the distalend, covering the now non-embedded distal portion of the electrode witha second matrix material by, for instance, taking recourse to a sheathapplied on the non-embedded distal portion, filling the sheath with asolution or suspension of the second matrix material, evaporating thesolvent so as to dry/harden the second matrix material, and removing thesheath.

Defined compartments within the matrix containing releasable bioactivemolecules can be achieved so as to focus the drug effects to the tipregions or to the shank region of the electrodes. This can be achievedby manufacturing the matrix—electrode construction in two or more steps,each step adding on a compartment.

Materials and Dimensions

Electrode Dimensions.

The electrodes of the invention have a suitable diameter of from 10⁻⁴ to10⁻⁷ m, in particular of from 0.5 to 25 μm. A larger wire diameter, suchas up to 1.5×10⁻³ m may be used in case a gross stimulation/recordingparadigm is used, for example to produce lesions in soft tissue. Theirdiameter may change over their length to facilitate insertion into thetissue, in particular the electrode can be tapering towards their distalend. Their distal end can be sharp or blunt but a sharp tip is preferredin case of the electrode being used for recording of electricalactivity. Their distal part may even have a diameter smaller than 10⁻⁷m.

The surface of electrodes may be smooth or not or partially smooth andpartially not smooth, that is, rough. An uneven or rugged surface closeto the electrode tip is preferred for improving the anchoring propertiesand for reducing the impedance of the electrode tip. The electrode ofthe invention is preferably insulated except for at portions extendingfrom their proximal and distal ends. However, the electrode body mayalso be equipped with means to allow stimulation/recordings at multiplessites within the tissue. Such means may, for example, consist ofelectrically conductive protruding ultra-thin filaments, or portionswith a rough or uneven surface occupying a length of up to 10 μm ormore. Such regions are not electrically insulated if an electricalcontact with the tissue is intended. They may also serve as anchoringmeans and, in addition, as for electrical stimulation/recording. Ifelectrical stimulation of a larger volume of tissue is intended, it isalternatively preferred not to insulate a larger portion extending fromthe electrode tip, such as a length of up to 100 μm or even up to 1 mm.Suitable for insulation of the electrode wires are, for instance, glass,polyvinyl formal, parylene C, polyxylene, epoxi resin, polyamide,silicon rubber, water-insoluble lacquer.

Electrode Shape.

An important feature of the present invention is that the distance fromthe distal tip to the proximal coupling section of the electrode can berepetitively and reversibly increased and decreased without rupture ofthe electrode so as to permit the wire to smoothly follow non-uniformmovements in surrounding soft tissue, such as may occur in the vicinityof arterial or venous vessels, the heart or the lungs or between softand hard tissue. This is achieved by equipping the electrode withmultiple bends, which may follow a given pattern or not. The electrodesthus can have a wavy, curly, tortuous, spiral or otherwise not straightconfiguration, which allows the distance from the proximal couplingsection to the distal tip section to be easily increased/decreased by atleast 1%, but preferably by at least 5% when force is exerted along thewire. For example, the distance from tip to base of an electrode of 1 mmin length can be easily increased/decreased by at least 10 μm, and evenby 50 μm or more.

It is preferred to use a smooth bending pattern, such as a wavy orspiral pattern. A pattern characterized by abrupt bends is lesspreferred, since the forces caused by increasing/decreasing the distancebetween the tip and the proximal coupling section of the electrodeshould not substantially affect particular sites on or short sectionsalong the electrode body, but should rather affect larger sections. Thiswill increase the endurance of an electrode exposed to continuouschanges in length by the movement of surrounding living tissue. Althoughnot preferred, it is within the ambit of the invention to use elasticconductive wires coated with an elastic insulation material, such assilicone rubber. Moreover, other types of electrodes, such as straightelectrode wires or electrodes mounted on flexible chips, may be used intissue regions that do not exhibit substantial movement along theelectrode axis.

Electrode Materials.

To approach the ratio of electrode density to tissue density, andthereby reduce the difference in inertia between the electrode and thetissue, the electrode of the invention comprises a core of a light andstrong nonconductive material such as natural protein fibre, forinstance silk, or polymer fibre covered by an electrically conductivematerial. Alternatively a tubiform supportive material filled with anelectrically conductive material such as a metal, in particular a noblemetal or a noble metal alloy, but also carbon may be used; in this casethe supportive material may additionally act as an electrical insulator.Other examples of useful non-conductive core or tubiform supportingmaterials are glass and ceramic. The electrically conductive materialcan be deposited on the support material by conventional sputtering orevaporation techniques. Optionally, the electrode of the invention cancomprise an electrically conductive metal core of, in particular, gold,platinum, titanium, stainless steel, an alloy comprising more than 30%by weight of noble metal such as iridium, the combination of platinumand iridium, and tungsten, but also of an electrically conductivepolymer.

Exemplary Uses

Preferred uses of the electrode of the invention as well as bundles ofthe electrode of the invention and arrays of the electrode of theinvention and/or of bundles of the electrode of the invention aredescribed in the following.

Clinical Use.

For aiding patients after brain/spinal damage by recording signals fromremaining neurons in case of, for instance, stroke or degenerativedisease and/or stimulating neurons to compensate for lost functions.Similar uses are possible in animals. In particular: pain relief bystimulation of analgesic brain stem centres, such as nuclei in theperiaqueductal grey substance; relief or decrease of tremor inParkinson's disease, choreatic and other involuntary movements bystimulation within the basal ganglia or associated nuclei; boostingmemory by stimulation of cholinergic and/or monoaminergic nuclei in caseof Alzheimer's disease or other degenerative diseases; control of mood,aggression, anxiety, phobia, affect, sexual over-activity, impotence,eating disturbances by stimulation of limbic centers or other brainareas; rehabilitation of patients after stroke or damage of thebrain/spinal cord by stimulation of remaining connections in the cortexcerebri or descending motor pathways; re-establishment of control ofspinal functions such as bladder and bowel emptying after spinal cordinjury by stimulating relevant parts in the spinal cord; control ofspasticity by stimulation of inhibitory supraspinal descending centresor appropriate cerebellar areas; re-establishment of somatosensory,auditory, visual, olfactory senses by stimulation of relevant nuclei inthe spinal cord and the brain. Other medical uses are also within theambit of the invention.

Examples where recording is combined with stimulation include but arenot limited to: monitoring of epileptic attacks by electrodes implantedinto the epileptic focus—coupled to a system that deliver antiepilepticdrugs or electrical pulses; compensating for lost connections in themotor system by recording central motor command and stimulating theexecutive parts of the motor system distal to the lesions; recordings ofblood glucose levels to control the release of hormones. Implantedelectrodes of the invention may also be used for local lesioning oftissue by passing current of sufficient magnitude through theelectrodes. The multichannel design offers a possibility to selectivelylesion particular areas in the tissue. This can be useful if a tumour oran abnormally active or epileptogenic nervous tissue has to be lesioned.In such cases, the electrodes may first be used to record and locate thedisease followed by stimulation. The invention also permits combinedlocal drug administration and stimulation as a therapy for treatingcancer. Lesioning of tissue by passing current through the electrodesmay also be combined with drug delivery, for example of growth factorsprior to implantation of new tissue to create a favourable situation forthe new implant.

It is also possible to combine stimulation and recording with release ofembedded analgesics or antiepileptic drugs, embedded drugs such asneurotrophic substances, antioxidants or drugs antagonizing apoptosis tohalt or alleviate disease processes. Combined stimulation and release oftrophic factors can also be used to trigger regenerative processes andlearning mechanisms (similar to what is seen during development) withthe aim of guiding functional recovery.

Use in Research and Drug Development.

To study the normal and pathological functions of the brain and spinalcord, it is necessary to be able to record neuronal activity and, at thesame time, interact with the undisturbed central nervous system (CNS).For this purpose, the electrodes, electrode bundles and arrays ofelectrode bundles of the invention will have to be implanted in CNS fora long time. Due to their design and dimensions they can be leftsecurely in the CNS for a very long time. The invention permitscontinuous measurements of the neuronal in any of the different braincenters to gauge the function, activation pattern, and abnormal activityin the center. These measurements can then be used to test the effectsof various bioactive molecules administrated systemically or locally.Bioactive molecules include substances acting, for example, throughreceptor activation but also vector systems mediating gene transfer. Byinducing the expression of specific genes in cells in the neighbourhoodof the electrode(s) effect equivalent to pharmacological treatment canbe achieved of extended periods of time, such as days and even weeks,and many fundamental cell properties can be permanently altered forexperimental or therapeutic purposes.

For example, the electrodes may be used to monitor pain related signalsfor a long time in nociceptive pathways to the cortex cerebri in animalmodels of pain. Moreover, due to its embedded drugs it is possible toreduce the complications that may occur during and after implantationsuch as bleedings, infections, inflammation, apoptosis etc, and which,if left unattended, would have complicated the interpretation of theresults from the electrodes.

The electrodes of the invention may also be used to record and stimulatenerve fibers or their somata in the peripheral nervous system (PNS).

Combinations of electrical stimulation/recordings and drug delivery arealso possible. Due to that the embedded means for local drug deliveryare configurationally locked to the electrodes during implantation, itis possible to embed a variety of bioactive molecules and measure theirlocal and distant effects on the tissue.

A particularly useful application is to use the invention to measure theeffects on the central nervous system and peripheral nervous system ofmany different types of bioactive molecules simultaneously. This can beachieved if the coating of different electrodes of the inventioncontains different bioactive molecules/drugs since these drugs will bereleased close to the respective electrodes. Using bundles of electrodesor arrays of electrodes/bundles of electrodes where individual recordingelectrodes are coated with different bioactive molecules opens uppossibilities for high performance screening of the effects of multiplepotentials therapeutic drugs. Such a screening of potential drugs mayalso be used in combination with electrical stimulation or stimulationproduced release of bioactive molecules. For example, it is possible tosimultaneously record the effects of different bioactive molecules onpathological activity caused by either active or passive local releaseof neurotoxins from embedded drug compartments.

Combined recording and release of key molecules can be used to studyphysiological effects of molecular manipulations in intact functionalcircuits—such as manipulations of signalling pathways in plasticitypathways underlying learning in natural situations.

Voltametric measurements of concentrations of specific physiologicallyor pharmacologically relevant molecules (time resolution in ms). Thiswill make it possible to follow the local effect of e.g. a drug onconcentrations of specific molecules in real time in intact behavinganimals. Combined measurements of the release of transmitter substance(such as dopamine, serotonin, noradrenalin, acetylcholine, neuropeptidesetc) and recordings/stimulations can be used to study disease processes.Measurements of release may also be used to construct feedback systems.For example, by measuring the release of dopamine it is possible toconstruct a system that stimulate the dopaminergic neurons when theyunder-perform.

The invention can be used to combat bleedings during surgery or afterstroke—by a combination of electrical stimulation that coagulates thetissue and local release of drugs producing vasoconstrictions andpromoting coagulations during bleedings.

Use as an Interface for Interaction with Computers and NeuroprostheticDevices.

In patients with damage to the peripheral nervous system, it can beuseful to record command signals from CNS. These signals can then beinterpreted by computer programs and used to guide activity inneuroprostheses, such as artificial hands or feet, guide stimulation ofmuscles and organs such as the bladder and bowel. Implanted electrodesof the invention may also be used to monitor the health status of forexample patients undergoing surgery, disabled or senile patients and beconnected with health surveillance systems to improve patient care. Theelectrodes of the invention can, either through wire-connections ortelemetric equipment, communicate with measurement equipment of variouskind, such as amplifiers, stimulators and computers.

Use in Controlling the Function of Endocrine and Exocrine Organs.

In patients with a deficient hormone secretion or regulation, theelectrode, electrode bundle or array of electrodes and/or electrodebundles of the invention may be used to control the secretion ofhormones from exocrine or endocrine organs or brain structurescontrolling such organs, for example the hypothalamus and certain brainstem nuclei. Combinations of drug delivery and electricalstimulation/recordings may be useful in scientific studies of neuronalsystems and in studies of tissue reactions.

What is claimed is:
 1. A medical microelectrode bundle comprising atleast two medical microelectrodes configured to be inserted into softtissue, each medical microelectrode comprising: an electricallyconducting elongate electrode body comprising a first proximal end, anda second distal end, the electrode body comprising: a tip sectionextending from the distal end; a main body section extending in aproximal direction from the tip section, wherein the tip section, andthe main body section are embedded in a first electrode matrix section,which is substantially rigid, biocompatible and soluble or biodegradablein a body fluid; and a second electrode matrix section comprising atleast one of a sugar and agarose, and positioned such that at least asignificant part of the first electrode matrix section is positionedbetween the second electrode matrix section and the electrode main body,wherein a drug configured to be released upon dissolution orbiodegradation of the first electrode matrix element section comprisesthe first electrode matrix section or the second electrode matrixsection, wherein the at least two medical microelectrodes compriseelectrode bodies substantially disposed in parallel and sharing saidfirst electrode matrix section.
 2. The microelectrode bundle of claim 1,comprising a dissolution retardation coating on the shared firstelectrode matrix section.
 3. The microelectrode bundle of claim 1,wherein the proximal ends of the at least two medical microelectrodesare disposed in substantially the same plane.
 4. The microelectrodebundle of claim 1, comprising a coupling disposed at or near theproximal ends of the medical microelectrdoes.